Glycogen synthase kinase 3beta inhibitor, composition and process for the preparation thereof

ABSTRACT

Novel compounds having hydroxybenzoimidazole carboxylic amide are useful for inhibiting glycogen synthase kinase 3β (GSK-3β).

FIELD OF THE INVENTION

The present invention relates to a compound for inhibiting glycogensynthase kinase 3beta (GSK-3β) activity, a pharmaceutical compositioncontaining the compound as an active ingredient and a process for thepreparation thereof.

BACKGROUND OF THE INVENTION

Glycogen synthase kinase 3 (GSK-3), the well-known target protein forthe treatment of diabetes and dementia, is a serine/threonine proteinkinase which inhibits the activity of glycogen synthase (GS) by way ofphosphorylation.

In the fatty tissue of mice suffering from fatty diabetes, the GSK-3βactivity has been observed to be 2 fold higher than that of a normalmouse (H. Eldar-Finkelman, Diabetes, 48:1662-1666 (1999)) and patientsduring the second type diabetes are characterized by a high expressionlevel of GSK-3β than normal (S. E. Nikoulina et al., Diabetes, 49:263-171 (2000)). Also, the GSK-3β activity in the brain of a dementiapatient is high (Yamaguchi H. et al., Acta. Neuropathol., 92: 232-241(1996)), and transgenic mice programmed to express GSK-3β in the brainhave abnormal neurons caused by hyperphosphorylating tau of theneurofibrillary tangle which plays an important role in the dementiaattack (Lucas J. J. et al., EMBO J. 20: 27-39 (2001)).

GSK-3β is further related to bipolar disorder which can be treated bylithium and valproic acid, well-known GSK-3β inhibitors (Elahi S. etal., J. Infect. Dis. 176: 217-226 (1997)).

Thus, there has existed a need to develop an effective inhibitor ofGSK-3β for treating or preventing GSK-β-dependent diseases.

The present inventors have endeavored to develop an effective inhibitorof GSK-3β; and have unexpectedly found that a compound containing ahydroxybenzoimidazole carboxylic amide moiety can inhibit the activityof GSK-3β, and therefore, can be used for treating or preventingGSK-β-dependent diseases such as fatness, diabetes and dementia.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide aGSK-3β inhibitor having high inhibitory activity against GSK-3β.

It is another object of the present invention to provide a process forpreparing said inhibitor.

It is further object of the present invention to provide apharmaceutical composition for inhibiting GSK-3β.

In accordance with one aspect of the present invention, there isprovided a compound of formula (I), a pharmaceutically acceptable salt,hydrate, solvate or isomer thereof:

wherein:

n is 0, 1, 2 or 3;

R¹, R² and R³ are each independently hydrogen, hydroxy, halogen ormorpholin-1-yl-ethylamino;

R⁴ and R⁵ are each independently hydrogen;

linear or cyclic C₁-C₆ alkyl optionally having one or more substituents,the carbon of the alkyl being optionally replaced with nitrogen, sulfuror oxygen, wherein the substituent is: hydroxy; halogen; alkyloxy;alkyl; amino; alkylamino; carboxyl; nitro; sulfonylamido;alkanesulfonyl; amido; an aromatic group optionally having one or moresubstituents selected from the group consisting of hydroxy, halogen,alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro, amido,dioxoisoindole and sulfonylamino; an aromatic group having one or moresubstituents selected from the group consisting of hydroxy, halogen,alkyloxy, alkyl, amino, alkylamino, carboxyl, nitro and amido, thearomatic ring having nitrogen, sulfur or oxygen; or cyclic C₃-C₈ alkyloptionally having one or more substituents selected from the groupconsisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino,carboxyl, nitro and amido;

an aromatic group optionally having one or more substituents, thearomatic ring having optional nitrogen, sulfur or oxygen, wherein thesubstituent is; hydroxy; halogen; alkyloxy; alkyl; amino; alkylamino;carboxyl; nitro; sulfonylamido, alkanesulfonyl; amido; or linear orcyclic C₁-C₆ alkyl optionally having one or more substituents, the alkylhaving an optional nitrogen, sulfur or oxygen linkage and the substiuentof the alkyl being: hydroxy; halogen; alkyloxy; alkyl; amino;alkylamino; carboxyl; nitro; sulfonylamido, alkanesulfonyl; amido; anaromatic group optionally having one or more substituents selected fromthe group consisting of hydroxy; halogen; alkyloxy; allyl; amino;alkylamino; carboxyl; nitro; amido; dioxoisoindole; and a sulfonylaminohaving an aromatic group substituted with hydroxy, halogen, alkyloxy,alkyl, amino, alkylamino, carboxyl, nitro, sulfonylamido, alkanesulfonylor amido; an aromatic group optionally having one or more substituentsselected form the group consisting of hydroxy, halogen, alkyloxy, alkyl,amino, alkylamino, carboxyl, nitro, sulfonylamide, alkanesulfonyl andamido, the aromatic ring containing nitrogen, sulfur or oxygen; or acyclic C₃-C₈ alkyl optionally having one or more substituents selectedfrom the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino,alkylamino, carboxyl, nitro and amido; or

form, together with the —N—(CH₂)_(n)— moiety to which they are attached,a nitrogen heterocycle optionally having one or more substituentsselected from the group consisting of OH, NH₂, NO₂, the heterocyclecontaining optional nitrogen or oxygen.

DETAILED DESCRIPTION OF THE INVENTION

Among the compounds of formula (I) of the present invention, thepreferred are:

those wherein n, R¹, R² and R³ have the same meaning as definedpreviously;

R⁴ and R⁵ are each independently hydrogen;

C₁-C₄ alkyl optionally having one or more substituents selected from thegroup consisting of OH, NH₂, NO₂, and an aromatic group, the aromaticgroup optionally having one or more substituents selected from the groupconsisting of OH, C₁-C₄ alkyloxy, NH₂, NO₂, methanesulfonylamino,ethanesulfonylamino, tolunensulfonylamino and dioxoisoindole; cyclicC₃-C₈ alkyl optionally having one or more substituents selected from thegroup consisting of OH, NH₂ and NO₂; C₁-C₄ alkyl carrying a morpholineor oxopyrolidine group which is optionally substituted with OH, NH₂, NO₂or —O—; C₁-C₄ alkyl or C₁-C₄ aminoalkyl carrying a pyrrol, pyrazole,imidazole, 1,2,3-triazole, 1,2,4-triazole, isoxazole, oxazole,isotiazole, tiazolidine, tiazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole,1,2,5-thiodiazole, 1,2,3-thiodiazole, 1,3,4-oxadiazole,1,3,4-thiodiazole, pyridine, pyrimidine or triazine group which isoptionally having one or more substituents selected from the groupconsisting of Cl, OH, NH₂, NO₂, C₁-C₄ and phenyl;

cyclic C₃-C₈ alkyl optionally having one or more substituents selectedfrom the group consisting of OH, NH₂ and NO₂;

an aromatic group optionally having one or more substituents selectedfrom the group consisting of OH; NH₂; hydroxyalkyl; aminoalkyl; NO₂; anda C₁-C₄ alkyl group optionally having one or more substituents selectedfrom the group consisting of OH, NH₂, NO₂, methanesulfonylamino,ethanesulfonylamino, tolunensulfonylamino, dioxoisoindole andthiophensulfonylamino; or

form, together with the —N—(CH₂)_(n)— moiety to which they are attached,a nitrogen heterocycle optionally having one or more substituentsselected from the group consisting of OH, NH₂ and NO₂, the heterocyclecontaining 1 to 3 nitrogen, sulfur or oxygen atom.

In the present invention, the compounds of formula (I) as the below aremost preferred:

those wherein n, R¹, R² and R³ have the same meaning as definedpreviously;

R⁴ and R⁵ are each independently hydrogen;

C₁-C₄ alkyl optionally having one or more substituents selected from thegroup consisting of OH, NH₂, NO₂, morpholine, nitropyridineamino,pyridine, oxopyrolidin, imidazole optionally having a Cl, CH₃ or phenylsubstituent; and phenyl optionally having one or more substituentsselected from the group consisting of OH, NH₂, methoxy, NO₂,methanesulfonylamino, ethanesulfonylamino, tolunensulfonylamino anddioxoisoindole;

cyclic C₃-C₈ alkyl optionally having one or more substituents selectedfrom the group consisting of OH, NH₂ and NO₂;

phenyl optionally having one or more substituents selected from thegroup consisting of OH; NH₂; NO₂; and C₁-C₄ alkyl optionally having aOH, NH₂, NO₂, methanesulfonylamino, ethanesulfonylamino,tolunensulfonylamino, dioxoisoindole or thiophensulfonylaminosubstituent; or

form, together with —N—(CH₂)_(n)— moiety to which they are attached, apiperidine ring optionally having one or more substituents selected fromthe group consisting of OH, NH₂ and NO₂.

Important compounds of the present invention are listed in Table 1below. TABLE 1 Com No. R¹ R² R³ R⁴ R⁵  1 0 H H H H H  2 0 H H H H Phenyl 3 0 H H H H 4-hydroxyphenyl  4 0 H H H H 4-aminophenyl  5 0 H H H H4-hydroxycyclohexyl  6 0 H H H H 4-(hydroxymethyl)phenyl  7 0 H H H H4-(hydroxyethyl)phenyl  8 0 H H H H 4-(aminoethyl)phenyl  9 0 H H H H4-(p-toluenesulfonamidylethyl)phenyl  10 0 H H H H4-(methanesulfonamidylethyl)phenyl  11 0 H H H H4-(phthalinidylethyl)phenyl  12 0 H H H H4-(2-thiophenylsulfonamidylethyl)phenyl  13 0 H H H H4-(ethansulfonamidylethyl)phenyl  14 0 H H Cl H phenyl  15 0 H H Cl H4-hydroxycyclohexyl  16 0 H H Cl H 4-(p-toluenesulfonamidylethyl)phenyl 17 0 H H Cl H 4-(methanesulfonamidylethyl)phenyl  18 0 H H Cl H4-(phthalinidylethyl)phenyl  19 0 H H Cl H4-(2-thiophenylsulfonamidylethyl)phenyl  20 0 H H Cl H4-(ethansulfonamidylethyl)phenyl  21 0 Cl H Cl H H  22 0 Cl H Cl HPhenyl  23 0 Cl H Cl H 4-hydroxycyclohexyl  24 0 Cl H Cl H4-(aminoethyl)phenyl  25 0 Cl H Cl H 4-aminophenyl  26 0 Cl H Cl H4-(hydroxymethyl)phenyl  27 0 Cl H Cl H 4-(hydroxyethyl)phenyl  28 0 ClH Cl H 4-(p-toluenesulfonamidylethyl)phenyl  29 0 Cl H Cl H4-(methanesulfonamidylethyl)phenyl  30 0 Cl H Cl H4-(phthalinidylethyl)phenyl  31 0 Cl H Cl H4-(2-thiophenylsulfonamidylethyl)phenyl  32 0 Cl H Cl H4-(ethansulfonamidylethyl)phenyl  33 0 H H F H4-(methanesulfonarnidylethyl)phenyl  34 0 H H F H4-(p-toluenesulfonamidylethyl)phenyl  35 0 H H F H4-(ethansulfonamidylethyl)phenyl  36 0 H H F H 4-morpholinophenyl  37 0F H F H 4-(methanesulfonamidylethyl)phenyl  38 0 F H F H4-(p-toluenesulfonamidylethyl)phenyl  39 0 F H F H4-(ethanesulfonamidylethyl)phenyl  40 0 Cl H F H4-(p-toluenesulfonamidylethyl)phenyl  41 0 Cl H F H4-(methanesulfonamidylethyl)phenyl  42 0 Cl H F H4-(ethanesulfonamidylethyl)phenyl  43 0 H Cl F H4-(p-toluenesulfonamidylethyl)phenyl  44 0 H Cl F H4-(ethanesulfonamidylethyl)phenyl  45 0 H Cl F H4-(methanesulfonamidylethyl)phenyl  46 0 H H H R⁴, R⁵ = piperidinyl  470 H H Cl R⁴, R⁵ = piperidinyl  48 0 Cl H Cl R⁴, R⁵ = piperidinyl  49 1 HH H H 4-nitrophenyl  50 1 H H H H 4-aminophenyl  51 1 H H H H phenyl  521 H H Cl H phenyl  53 1 H H Cl H 4-nitrophenyl  54 1 H H Cl H4-aminophenyl  55 1 Cl H Cl H phenyl  56 1 Cl H Cl H 4-nitrophenyl  57 2H H H H phenyl  58 2 H H H H 4-hydroxyphenyl  59 2 H H H H 4-nitrophenyl 60 2 H H H H 4-aminophenyl  61 2 H H H H amino  62 2 H H H H4-hydroxy-3-methoxyphenyl  63 2 H H H H 3-hydroxy-4-methoxyphenyl  64 2H H H H 4-(methanesulfonamidyl)phenyl  65 2 H H H H4-(p-toluenesulfonamidyl)phenyl  66 2 H H H H 4-morpholinyl  67 2 H H HH 4-phthlimidophenyl  68 2 H H H ll 4-(ethanesulfonamidyl)phenyl  69 2 HH H H 4-nitro-2-pyridinylamino  70 2 H H H H 2-pyridyl  71 2 H H Cl Hphenyl  72 2 H H Cl H 4-nitrophenyl  73 2 H H Cl H 4-aminophenyl  74 2 HH Cl H 4-hydroxyphenyl  75 2 H H Cl H 4-(methanesulfonamidyl)phenyl  762 H H Cl H 4-(p-toluenesulfonamidyu)phenyl  77 2 H H Cl H3-hydroxy-4-methoxyphenyl  78 2 H H Cl H N-morpholinyl  79 2 H H Cl H4-phthalimidophenyl  80 2 H H Cl H 4-(ethanesulfonamidyl)phenyl  81 2 HH Cl H 4-nitro-2-pyridinylamino  82 2 H H Cl H 2-pyridyl  83 2 H H Cl H4-imidazolyl  84 2 H H Cl H 4-hydroxyphenyl  85 2 H H Cl H4-acetylamino-2-pyridylamino  86 2 H H Cl H 4-(4-methylpiperazin-1-yl-acetylamino)phenyl  87 2 H H Cl H 4-(4-ethylpiperazin-1-yl-acetylamino)-phenyl  88 2 H H Cl H 4-(dimethylaminoacetylamino)phenyl  89 2 H H Cl H4-(diethylaminoacetylamino)phenyl  90 2 H H Cl H 4-aminophenyl  91 2 H HCl H 4-amino-2-pyridylamino  92 2 H H Cl H4-(morpholin-4-yl-acetylamino)phenyl  93 2 H H Cl H4-(N,N-dimethylamino)phenyl  94 2 H H Cl H4-(morpholin-4-yl-ethoxy)phenyl  95 2 H H Cl H4-(4-methylpiperazin-1-yl-ethoxy)phenyl  96 2 H H Cl H 2-hydroxyphenyl 97 2 H H Cl H 2-methoxyphenyl  98 2 H H Cl H 3-bromophenyl  99 2 Cl HCl H phenyl 100 2 Cl H Cl H 4-nitrophenyl 101 2 Cl H Cl H4-hydroxy-3-methoxyphenyl 102 2 Cl H Cl H 3-hydroxy-4-methoxyphenyl 1032 Cl H Cl H amino 104 2 Cl H Cl H 4-hydroxyphenyl 105 2 Cl H Cl H4-(p-toluenesulfonamidyl)phenyl 106 2 Cl H Cl H4-(methanesulfonamidyl)phenyl 107 2 Cl H Cl H 4-phthlimidophenyl 108 2Cl H Cl H 4-morpholinyl 109 2 Cl H Cl H 4-(ethanesuffonamidyl)phenyl 1102 Cl H Cl H 4-nitro-2-pyridinylamino 111 2 Cl H Cl H 2-pyridyl 112 2 ClH Cl H 4-(acetylaniino)phenyl 113 2 Cl H Cl H 4-(pentanoylamino)phenyl114 2 H H F H 4-(methanesulfonamidyl)phenyl 115 2 H H F H4-(p-toluenesulfonamidyl)phenyl 116 2 H H F H4-(ethanesulfonamidyl)phenyl 117 2 H H F H 4-(acetylamino)phenyl 118 2 HH F H 4-methylpiperazin-1-yl 119 2 H H F H 4-morpholin-1-yl 120 2 H H FH 4-(pentanoylamino)phenyl 121 2 H H F H 4-hydroxyphenyl 122 2 H H F H4-nitro-2-pyridinylamino 123 2 H H F H4-(methanesulfonylamino-2-pyridyl)amino 124 2 H H F H4-(p-toluenesulfonylamino-2-pyridyl)- amino 125 2 H H F H 4-imidazolyl126 2 H H F H 4-acetylamino-2-pyridylamino 127 2 H H F H4-(4-methylpiperazin-1-yl- acetylamino)phenyl 128 2 H H F H4-(4-ethylpiperazin-1-yl-acetylamino)- phenyl 129 2 H H F H4-(dimethylaminoacetylamino)phenyl 130 2 H H F H4-(diethylaminoacetylamino)phenyl 131 2 H H F H 4-aminophenyl 132 2 H HF H 4-morpholmophenyl 133 2 H H F H4-(3-dimethylaminopyrrolidin-1-yl)phenyl 134 2 H H F H4-(morpholin-4-yl-acetylamino)phenyl 135 2 H H F H4-(N,N-dimethylamino)phenyl 136 2 H H F H4-(morpholin-4-yl-ethoxy)phenyl 137 2 H H F H 2-hydroxyphenyl 138 2 H HF H 2-methoxyphenyl 139 2 H H F H 3-bromophenyl 140 2 F H F H4-(methanesulfonamidyl)phenyl 141 2 F H F H4-(p-toluenesulfonamidyl)phenyl 142 2 F H F H4-(ethanesulfonamidyl)phenyl 143 2 Cl H F H4-(methanesulfonamidyl)phenyl 144 2 Cl H F H4-(p-toluenesulfonamidyl)phenyl 145 2 Cl H F H4-(ethanesulfonamidyl)phenyl 146 2 Cl H F H 4-(acetylamino)phenyl 147 2Cl H F H 4-morpholin-1-yl 148 2 Cl H F H 4-methylpiperazin-1-yl 149 2 ClH F H 4-(pentanoylamino)phenyl 150 2 Cl H F H 4-hydroxyphenyl 151 2 Cl HF H 4-nitro-2-pyridinylamino 152 2 Cl H F H4-(methanesulfonylamino-2-pyridyl)amino 153 2 Cl H F H4-(p-toluenesulfonylamino-2-pyridyl)- amino 154 2 Cl H F H 4-imidazolyl155 2 Cl H F H 4-acetylamino-2-pyridylamino 156 2 Cl H F H4-(4-methylpiperazin-1-yl acetylamino)phenyl 157 2 Cl H F H4-(4-ethylpiperazin-1-yl-acetylamino) phenyl 158 2 Cl H F H4-(dimethylaminoacetylamino)phenyl 159 2 Cl H F H4-(diethylaminoacetylamino)phenyl 160 2 H Cl F H4-(p-toluenesulfonamidyl)phenyl 161 2 H Cl F H4-(methanesulfonamidyl)phenyl 162 3 H H H H methyl 163 3 H H H H amino164 3 H H H H 2-oxopyrrolidin-1-yl 165 3 H H H H 1-imidazolyl 166 3 H HH H 4-N-morpholmyl 167 3 H H H H 2-methylimidazol-1-yl 168 3 H H Cl Hmethyl 169 3 H H Cl H 2-oxopyrrolidin-1-yl 170 3 H H Cl H 1-imidazolyl171 3 H H Cl H 4-morpholinyl 172 3 H H Cl H 2-phenylimidazol-1-yl 173 3H H Cl H 4-methylimidazol-1-yl 174 3 H H Cl H 4,5-dichloroimidazo-1-yl175 3 H H Cl H 2-methylimidazol-1-yl 176 3 Cl H Cl H methyl 177 3 Cl HCl H 2-oxopyrrolidin-1-yl 178 3 Cl H Cl H 1-imidazolyl 179 3 Cl H Cl H4-morpholin-yl 180 3 Cl H Cl H 2-phenylimidazol-1-yl 181 3 Cl H Cl H4-methylimidazol-1-yl 182 3 Cl H Cl H 4,5-dichloroimidazol-1-yl 183 3 ClH Cl H 2-methylimidazol-1-yl 184 3 Cl H Cl H 2-isopropylimidazol-1-yl185 3 H H F H 1-imidazolyl 186 3 H H F H 2-isopropylimidazol-1-yl 187 3H H F H 4-methylimidazol-1-yl 188 3 H H F H 2-methylimidazol-1-yl 189 3H H F H 2-ethylimidazol-1-yl 190 3 H H F H 4,5-dichloroimidazol-1-yl 1913 F H F H 2-isopropylimidazol-1-yl 192 3 F H F H 1-imidazolyl 193 3 F HF H 4-methylimidazol-1-yl 194 3 F H F H 4,5-dichloroimidazol-1-yl 195 3F H F H 2-methylimidazol-1-yl 196 3 F H F H 2-ethylimidazol-1-yl 197 3 FH F H 4,5-dichioroimidazol-1-yl 198 3 Cl H F H 1-imidazolyl 199 3 Cl H FH 4-methylimidazol-1-yl 200 3 Cl H F H 4,5-dichloroimidazol- 1-yl 201 3Cl H F H 2-methylimidazol- l-yl 202 3 H Cl F H 4-methylimidazol-1-yl 2033 H Cl F H 1-imidazolyl 204 3 R¹, R² and R⁴ = H4,5-dichloroimidazol-1-yl R³ = morpholin- 1-yl-ethylamino

The inventive compound (except for the compound wherein R³ ismorpholin-1-yl-ethylamino) of formula (Ia) may be prepared as in Scheme1.

wherein, p-TSA is p-toluenesulfonic acid, DMF is dimethylformamide, THFis tetrahydrofuran, TFA is trifluoroacetic acid, EDCI isethyl-dimethylaminopropyl-carbodiimide hyrochloride, DMAP is4-dimethylaminoprydine, HOBt is N-hydroxybezotriazole, n, R¹, R², R³, R⁴and R⁵ have the same meaning as defined previously.

As shown in Scheme I, the compound of formula (Ia) can be prepared byreacting 3-amino-4-methoxy benzoic acid (compound II) and an alcohol(e.g., methanol or ethanol) to obtain compound (III); adding anhydrousp-toluenesulfonic acid and benzonitrile to the compound (III) thusobtained, refluxing the mixture at 80 to 200° C., adding NaOCl theretoat room temperature and purifying by silica gel column chromatography toobtain compound (IV); dissolving the compound (IV) thus obtained in analcohol (e.g., methanol or ethanol), adding an aqueous alkali solution(Na₂CO₃, NaHCO₃, K₂CO₂ or KHCO₃ solution) thereto and refluxing themixture to obtain compound (V); dissolving the compound (V) thusobtained in an organic solvent, e.g., toluene, adding a Lewis acid(e.g., AlCl₃ or BBr₃) thereto and refluxing the mixture to obtaincompound (VI); dissolving the compound (V) thus obtained in an alcohol,adding a strong acid, nitric acid or sulfuric acid, thereto at roomtemperature and refluxing the mixture to obtain compound (VII);dissolving the compound (VII) thus obtained and(4-bromomethylphenoxy)-methyl polystyrene Wang resin in an organicsolvent, e.g., DMF, THF or chloroform, adding a base (CsCO₃, Na₂CO₃,NaHCO₃, K₂CO₃ or KHCO₃) and KI thereto (1:3:3:3) and stirring themixture at 50 to 60° C. for 1 to 24 hours to obtain compound (VIII);dissolving the compound (VIII) thus obtained in an organic solvent,adding an alcohol solution of an alkali hydroxide (e.g., LiOH, NaOH orKOH) thereto and refluxing the mixture to obtain compound (IX);dissolving the compound (IX) thus obtained in an organic solvent, addingR⁴N(CH₂)_(n)R⁵ and a coupling agent (e.g., EDCI/DMAP/HOBt, DCC or pyBop)thereto and stirring the mixture at room temperature to obtain compound(X); and dissolving the compound (X) thus obtained in CH₂Cl₂, addingtrifluoroacetic acid thereto and stirring the mixture at roomtemperature to obtain compound (Ia).

The inventive compound (wherein R³ is morpholin-1-yl-ethylamino)represented to formula (Ib) may be prepared, as in Scheme II.

As shown in Scheme II, the compound of formula (Ib) can be prepared byreacting 3-amino-4-methoxy benzoic acid (compound II) and an alcohol(e.g., methanol or ethanol) to obtain compound (III), addingp-toluenesulfonic acid, benzene and 4-nitrobezonitrile thereto,refluxing the mixture at 80 to 200° C., adding NaOCl thereto at roomtemperature and purifying by silica gel column chromatography to obtaincompound (XI); dissolving the compound (XI) thus obtained in an organicsolvent, adding an aqueous alkali solution (e.g., Na₂CO₃ solution)thereto, refluxing the mixture and purifying by silica gel columnchromatography to obtain compound (XII); dissolving the compound (XII)thus obtained in an alcohol, adding Pd/C thereto and refluxing themixture to obtain compound (XIII); dissolving the compound (XIII) thusobtained in an organic solvent, adding a base (e.g., CsCO₃, Na₂CO₃,NaHCO₃, K₂CO₃ or KHCO₃), 2-chloroethylmorphine and potassium iodidethereto and stirring the mixture at room temperature to obtain compound(XIV); dissolving the compound (XIV) obtained thus in an organicsolvent, adding an alkali hydrate, stirring the mixture at roomtemperature to obtain compound (XV); dissolving the compound (XV) thusobtained in an organic solvent, adding4,5-dichloro-1-(3-aminoprophyl)imidazole and a coupling agent (e.g.,EDCI, DMAP or HOBt), stirring the mixture at room temperature andpurifying by silica gel column chromatography to obtain compound (XVI);and dissolving the compound (XVI) thus obtained in MC, adding a Lewisacid thereto, stirring the mixture, concentrating the resulting solutionunder a reduced pressure and purifying by silica gel columnchromatography to obtain compound (Ib).

A salt, hydrate, solvate and isomer of the inventive compound of formula(I) may be prepared by employing any of the known methods. The inventivecompound of formula (I), a salt, hydrate, solvate or isomer thereof mayused for the treatment of GSK-3β-dependent diseases including fatness,diabetes and dementia, by way of inhibiting GSK-3β activity, theinventive compound having an IC₅₀ value in the range of 1 to 10,000 nM.

Accordingly, the present invention includes a pharmaceutical compositionwhich comprises a therapeutically effective amount of the compound offormula (I), a salt, hydrate, solvate or isomer thereof as an activeingredient and a pharmaceutically acceptable carrier; therefore, thepharmaceutical composition of the present invention exerts superiorpreventive and treating effects on GSK-β-dependent diseases such asfatness, diabetes and dementia and the like.

A pharmaceutical formulation may be prepared in accordance with any ofthe conventional procedures. In preparing the formulation, the activeingredient is preferably admixed or diluted with a carrier, or enclosedwithin a carrier, sachet or other container. When the carrier serves asa diluent, it may be a solid, semi-solid or liquid material acting as avehicle, excipient or medium for the active ingredient. Thus, theformulations may be in the form of a tablet, pill, powder, sachet,elixir, suspension, emulsion, solution, syrup, aerosol, soft and hardgelatin capsule, sterile injectable solution, sterile packaged powderand the like.

Examples of suitable carriers, excipients, and diluents are lactose,dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose,methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone,water, methylhydroxybenzoates, propylhydroxybenzoates, talc, magnesiumstearate and mineral oil. The formulations may additionally includefillers, anti-agglutinating agents, lubricating agents, wetting agents,flavoring agents, emulsifiers, preservatives and the like. Thecompositions of the invention may be formulated so as to provide quick,sustained or delayed release of the active ingredient after theiradministration to a mammal by employing any of the procedures well knownin the art.

The pharmaceutical composition of the present invention can beadministered via various routes including oral, transdermal,subcutaneous, intravenous and intramuscular introduction. In case ofhuman, a typical daily dose of the compound of formula (I) may rangefrom about 0.01 to 100 mg/kg body weight, preferably 0.1 to 50 mg/kgbody weight, and can be administered in a single dose or in divideddoses. However, it should be understood that the amount of the activeingredient actually administered ought to be determined in light ofvarious relevant factors including the condition to be treated, thechosen route of administration, the age, sex and body weight of theindividual patient, and the severity of the patient's symptom; and,therefore, the above dose should not be intended to limit the scope ofthe invention in any way.

The following examples are intended to further illustrate the presentinvention without limiting its scope.

PREPARATION EXAMPLE 1 Preparation of Wang Resin (p-benzyloxybenzylAlcohol Resin)-Supported7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid (R¹═H, R²═H andR³═H) (1) Preparation of 3-amino-4-methoxy benzoic acid methyl ester

3-amino-4-methoxy benzoic acid (40 g, 0.239 mol) was dissolved inmethanol, H₂SO₄ (38.14 ml, 0.717 mol) was added dropwise thereto andrefluxed for 12 hours. The resulting mixture was cooled to roomtemperature and concentrated under a reduced pressure to removemethanol, neutralized with NaHCO₃, extracted with ethyl acetate, and theextract was concentrated under a reduced pressure. The resulting residuewas purified by recrystallization from ethyl acetate/hexane to obtainthe title compound (39 g, 0.215 mol) in a yield of 90%.

¹H NMR (CDCl₃): δ 7.87-7.78 (2H, m), 7.22 (1H, d), 3.93 (3H, s), 3.82(3H, s)

MW: 181

(2) Preparation of 4-methoxy-3-[(N-chloro-benzimidoyl)-amino]-benzoicacid methyl ester

Anhydrous p-toluene sulfonic acid (41.99 g, 220.8 mmol) was melted at120° C. and 3-amino-4-methoxy benzoic acid methyl ester (20 g, 110.38mmol) obtained in step 1 and benzonitrile (22.77 g, 220.8 mmol) wereadded thereto and stirred at 180° C. for 5 hours. The resulting solutionwas cooled to room temperature and the reaction was stopped by addingNaHCO₃ thereto. The resulting mixture was extracted with ethyl acetate,the extract was dried over MgSO₄ and concentrated under a reducedpressure. The concentrate was dissolved in 50% methanol and 5% NaOCl (56ml, 37.65 mmol) was added dropwise thereto. After 5 min, the resultingmixture was extracted with ethyl acetate, the extract was dried overMgSO₄ and concentrated under a reduced pressure. The resulting residuewas purified by silica gel column chlomatography(eluent—MeOH/CDCl₃=5:95, Merck, Silicagel 60) to obtain the titlecompound (31 g, 25.10 mmol) in a yield of 88%;

¹H NMR (CDCl₃): δ 7.78 (1H, d), 7.48(1H, s), 7.37-7.24 (5H, m), 6.95(1H, d), 3.78 (6H, s)

MW: 318

(3) Preparation of 7-methoxy-2-phenyl-1H-benzoimidazole-4-carboxylicacid methyl ester

4-methoxy-3-[(N-chloro-benzimidoyl)-amino]-benzoic acid methyl ester (8g, 25.10 mmol) obtained in step 1 was dissolved in 50 ml of 50% methanoland NaHCO₃ (5.32 g, 50.20 mmol) was added dropwise thereto at roomtemperature and refluxed for 5 min. The resulting solution was cooled toroom temperature, extracted with ethyl acetate, and the extract wasconcentrated under a reduced pressure. The resulting residue waspurified by recrystallization from ethyl acetate/hexane to obtain thetitle compound (6 g, 15.94 mmol) in a yield of 86%.

¹H NMR (CDCl₃): δ 10.65 (1H, br), 8.23 (2H, d), 7.49 (3H, m), 6.75 (1H,d), 4.13 (3H, s), 3.99 (3H, s)

MW: 282

(4) Preparation of 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylicacid

7-methoxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid methyl ester (4.5g, 15.94 mmol) obtained in step 3 was dissolved in 100 ml of toluene,aluminum chloride (9.56 g, 71.73 mmol) was added thereto and refluxedfor 8 hours. The resulting solution was cooled to room temperature, thereaction was stopped by adding 3 N HCl thereto and stirred for 30 min.The precipitate formed was filtered, washed with benzene and dried toobtain the title compound (3.5 g, 13.77 mmol) in a yield of 86%.

¹H NMR (DMSO-d₆): δ 8.29 (2H; d), 7.68 (1H, d), 7.56-7.49 (3H, m), 6.67(1H, d)

MW: 254

(5) Preparation of 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylicacid methyl ester

7-methoxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid (2.00 g, 7.46mmol) obtained in step 4 was dissolved in 30 ml of methanol, H₂SO₄ (2.00ml, 37.28 mmol) was added dropwise thereto and refluxed for 15 hours.The resulting solution was cooled to room temperature, concentratedunder a reduced pressure to remove methanol, and the residue wasneutralized with NaHCO₃. Then, the neutralized residue was extractedwith ethyl acetate and concentrated under a reduced pressure to obtain aresidue which purified by recrystallization from CHCl₃/MeOH/hexane toobtain the title compound (1.7 g, 5.89 mmol) in a yield of 83%.

¹H NMR (CH₃OH-d₄): δ 7.82 (1H, d), 7.42-7.25 (5H, m), 6.64 (1H, d), 4.92(3H, s)

MW: 268

(6) Preparation of Wang Resin (p-benzyloxybenzyl AlcoholResin)-Supported 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acidmethyl ester

p-nitrophenyl carbonate Wang resin (476 mg, 0.67 mmol) was dissolved inDMF, and 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid methylester (567 mg, 2.01 mmol) obtained in step 5, Cs₂CO₃ (655 mg, 2.01 mmol)and KI (334 mg, 2.01 mmol) were added thereto to be stirred at 50 to 60°C. for 12 hours. The resulting solution was cooled to room temperatureand filtered. The filtrate was washed with DMF, MeOH and CH₂Cl₂ anddried to obtain the title compound (608 mg, 0.65 mmol) in a yield of98%.

(7) Preparation of Wang Resin-Supported7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid methyl ester

Wang resin-supported 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylicacid methyl ester (570 mg, 0.47 mmol) obtained in step 6 was dissolvedin THF, LiOH.H₂O (99 mg, 2.35 mmol) in MeOH—H₂O (2:1) was added theretoand refluxed for 5 hours. The resulting solution was cooled to roomtemperature and filtered. The filtrate was washed with MeOH and CH₂Cl₂,and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of90%.

PREPARATION EXAMPLE 2 Preparation of2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (R¹═H,R²═H and R³═Cl) (1) Preparation of3-[(4-chloro-N-chloro-benzimidoyl)-amino]-4-methoxy-benzoic acid methylester

Anhydrous p-toluene sulfonic acid (41.99 g, 220.76 mmol) was melted at120° C. and 3-amino-4-methoxy benzoic acid methyl ester (20 g, 110.38mmol) obtained in step 1 of Preparation Example 1 and4-chlorobenzonitrile (22.78 g, 165.57 mol) were added thereto andstirred at 160° C. for 8 hours. The resulting solution was cooled toroom temperature and the reaction was stopped by adding 1M NaHCO₃thereto. The resulting mixture was extracted with ethyl acetate, theextract was dried over MgSO₄ and concentrated under a reduced pressure.The concentrate was dissolved in 500 ml of 50% methanol and 5% NaOCl(197 ml, 132.46 mmol) was added dropwise thereto. After 5 min, theresulting mixture was extracted with ethyl acetate, the extract wasdried over MgSO₄ and concentrated under a reduced pressure. Theresulting residue was purified by silica gel column chlomatography(eluent—MeOH:CDCl₃=5:95, Merck, Silicagel 60) to obtain the titlecompound (19.43 g, 55.19 mmol) in a yield of 50%.

¹H NMR (CH₃OH-d₄): δ 7.62 (2H, m), 7.22-7.15 (4H, m), 6.59 (1H, s),4.00-3.80 (6H, d)

MW: 352

(2) Preparation of2-(4-chloro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methylester

3-[(4-chloro-N-chloro-benzimidoyl)-amino]-4-methoxy-benzoic acid methylester (5.5 g, 15.63 mmol) obtained in step 1 was dissolved in 40 ml of50% methanol and Na₂CO₃ (3.53 g, 33.26 mmol) was added dropwise theretoat room temperature and refluxed for 5 min. The resulting solution wascooled to room temperature, extracted with ethyl acetate, the extractwas concentrated under a reduced pressure. The resulting residue waspurified by silica gel column chromatography to obtain the titlecompound (2.57 g, 8.13 mmol) in a yield of 52%.

¹H NMR (CDCl₃): δ 8.15 (2H, d), 7.95 (1H, d), 7.51 (2H, m), 6.75 (1H,d), 4.06 (3H, s)

MW: 316

(3) Preparation of2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

2-(4-chloro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methylester (1.0 g, 3.16 mmol) obtained in step 2 was dissolved in 10 ml oftoluene, aluminum chloride (2.11 g, 15.8 mmol) was added thereto andrefluxed for 8 hours. The resulting solution was cooled to roomtemperature, the reaction was stopped by adding 3 N HCl thereto andstirred for 30 min. The precipitate formed was filtered, washed withbenzene and dried to obtain the title compound (745 mg, 2.59 mmol) in ayield of 82%.

¹H NMR (CH₃OH-d₄): δ 8.06 (3H, m), 7.50 (2H, m), 6.97 (1H, d)

MW: 288

(4) Preparation of2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methylester

2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (200mg, 0.69 mmol) obtained in step 3 was dissolved in 5 ml of methanol,H₂SO₄ (0.18 ml, 3.45 mmol) was added dropwise thereto and refluxed for15 hours. The resulting solution was cooled to room temperature,concentrated under a reduced pressure to remove methanol, and theresidue was neutralized with 1M NaHCO₃. Then, the neutralized residuewas extracted with ethyl acetate and concentrated under a reducedpressure to obtain a residue which was purified by silica gel columnchromatography (eluent—MeOH/CDCl₃=5/95, Merck, Silicagel 60) to obtainthe title compound (166 mg, 0.55 mmol) in a yield of 80%.

¹H NMR (CH₃OH-d₄): δ 10.75 (1H, Br), 7.89 (3H, m), 7.46 (2H, d), 6.82(1H, d), 3.39 (3H, s)

MW: 302

(5) Preparation of Wang Resin-Supported2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methylester

(4-bromomethylphenoxy)-methyl polystyrene Wang resin (476 mg, 0.67 mmol)was dissolved in 5 ml of DMF, and2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methylester (567 mg, 2.01 mmol) obtained in step 4, Cs₂CO₃ (655 mg, 2.01 mmol)and KI (334 mg, 2.01 mmol) were added thereto to be stirred at 50 to 60°C. for 12 hours. The resulting solution was cooled to room temperatureand filtered. The filtrate was washed with DMF, MeOH and CH₂Cl₂ anddried to obtain the title compound (608 mg, 0.65 mmol) in a yield of98%.

(6) Preparation of Wang Resin-Supported2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

Wang resin-supported2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methylester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF,LiOH.H₂O (99 mg, 2.35 mmol) in MeOH—H₂O (1:1) was added thereto and theresulting mixture was refluxed for 5 hours. The resulting solution wascooled to room temperature and filtered. The filtrate was washed withMeOH and CH₂Cl₂, and dried to obtain the title compound (551 mg, 0.42mmol) in a yield of 90%.

PREPARATION EXAMPLE 3 Preparation of2-(2,4-dichloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid(R¹═Cl, R²═H and R³═Cl) (1) Preparation of3-[(2,4-dichloro-N-chloro-benzimidoyl)-amino]-4-methoxy-benzoic acidmethyl ester

Anhydrous p-toluene sulfonic acid (20.99 g, 110.04 mmol) was melted at120° C. and 3-amino-4-methoxy benzoic acid methyl ester (10 g, 55.20mmol) obtained in step 1 of Preparation Example 1 and2,4-dichlorobenzonitrile (18.99 g, 110.04 mol) were added thereto andstirred at 180° C. for 6 hours. The resulting solution was cooled toroom temperature and the reaction was stopped by adding NaHCO₃ thereto.The resulting mixture was extracted with ethyl acetate, the extract wasdried over MgSO₄ and concentrated under a reduced pressure. Theconcentrate was dissolved in 50% methanol and 5% NaOCl (30 ml, 20.64mmol) was added dropwise thereto. After 5 min, the resulting mixture wasextracted with ethyl acetate, the extract was dried over MgSO₄ andconcentrated under a reduced pressure. The resulting residue waspurified by silica gel column chromatography (eluent—MeOH:CDCl₃=5:95,Merck, Silicagel 60) to obtain the title compound (18 g, 10.32 mmol) ina yield of 84%.

¹H NMR (CDCl₃): δ 8.23 (1H, br), 7.75 (1H, d), 7.44 (1H, d), 7.36-7.26(2H, m), 7.03 (1H, s), 6.88 (1H, d), 3.96 (3H, s), 3.76 (3H, s)

MW: 318

(2) Preparation of2-(2,4-dichloro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acidmethyl ester

3-[(2,4-dichloro-N-chloro-benzimidoyl)-amino]-4-methoxy-benzoic acidmethyl ester (4 g, 10.32 mmol) obtained in step 1 was dissolved in 50 mlof 50% methanol and NaHCO₃ (2.19 g, 20.64 mmol) was added dropwisethereto at room temperature and refluxed for 5 min. The resultingsolution was cooled to room temperature, extracted with ethyl acetate,and the extract was concentrated under a reduced pressure. The resultingresidue was purified by recrystallization from ethyl acetate/hexane toobtain the title compound (3.2 g, 5.47 mmol) in a yield of 88%.

¹H NMR (CDCl₃): δ 8.54 (1H, d), 7.94 (1H, d), 7.48 (1H, s), 7.42 (1H,d), 6.76 (1H,d), 4.44 (3H, s), 3.99 (3H, s)

MW: 351

(3) Preparation of2-(2,4-dichloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

2-(2,4-dichloro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acidmethyl ester (1.9 g, 5.47 mmol) obtained in step 2 was dissolved in 100ml of toluene, aluminum chloride (3.61 g, 27.05 mmol) was added theretoand refluxed for 8 hours. The resulting solution was cooled to roomtemperature, the reaction was stopped by adding 3 N HCl thereto andstirred for 30 min. The precipitate formed was filtered, washed withbenzene and dried to obtain the title compound (1.63 g, 5.03 mmol) in ayield of 92%.

¹H NMR (DMSO-d₆): δ 8.19 (1H, d), 7.78 (1H, d), 7.62-7.55 (2H, m), 6.82(1H, d)

MW: 323

(4) Preparation of2-(2,4-dichloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acidmethyl ester

2-(2,4-dichloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid(1.63 g, 5.03 mmol) obtained in step 3 was dissolved in 30 ml ofmethanol, and H₂SO₄ (1.08 ml, 20.12 mmol) was added dropwise thereto andrefluxed for 15 hours. The resulting solution was cooled to roomtemperature, concentrated under a reduced pressure to remove methanol,and the residue was neutralized with NaHCO₃. Then, the neutralizedresidue was extracted with ethyl acetate and concentrated under areduced pressure to obtain a residue which was purified byrecrystallization from ethyl acetate/hexane to obtain the title compound(1.5 g, 3.62 mmol) in a yield of 86%.

¹H NMR (CDCl₃): δ 11.42 (1H, br), 8.21 (1H, d), 7.89 (1H, d), 7.56 (1H,s), 7.38 (1H, d), 6.82 (1H, d), 3.99 (3H, s)

MW: 337

(5) Preparation of Wang Resin-Supported2-(2,4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acidmethyl ester

p-nitrophenyl carbonate Wang resin (476 mg, 0.67 mmol) was dissolved inDMF, and2-(2,4-dichloro-phenyl)-7-hydroxy-2H-benzoimidazole-4-carboxylic acidmethyl ester (567 mg, 2.01 mmol), obtained in step 4, Cs₂CO₃ (655 mg,2.01 mmol) and KI (334 mg, 2.01 mmol) were added thereto to be stirredat 50 to 60° C. for 12 hours. The resulting solution was cooled to roomtemperature and filtered. The filtrate was washed with DMF, MeOH andCH₂Cl₂ and dried to obtain the title compound (608 mg, 0.65 mmol) in ayield of 98%.

(6) Preparation of Wang Resin-Supported2-(2,4-dichloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

Wang resin-supported2-(2,4-dichloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acidmethyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved inTHF, LiOH.H₂O (99 mg, 2.35 mmol) in MeOH—H₂O (2:1) was added thereto andthe resulting mixture was refluxed for 5 hours. The resulting solutionwas cooled to room temperature and filtered. The filtrate was washedwith MeOH and CH₂Cl₂, and dried to obtain the title compound (551 mg,0.42 mmol) in a yield of 90%.

PREPARATION EXAMPLE 4 Preparation of Wang Resin-Supported2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (R¹═H,R²═H and R³═F) (1) Preparation of3-[(4-fluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester

Anhydrous p-toluene sulfonic acid (41.99 g, 220.76 mmol) was melted at120° C. and 3-amino-4-methoxy benzoic acid methyl ester (20 g, 110.38mmol) obtained in step 1 of Preparation Example 1 and4-fluorobenzonitrile (20.00 g, 165.57 mol) were added thereto andstirred at 160° C. for 8 hours. The resulting solution was cooled toroom temperature and the reaction was stopped by adding NaHCO₃ thereto.The resulting mixture was extracted with ethyl acetate, the extract wasdried over MgSO₄ and concentrated under a reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent—MeOH:CDCl₃=5:95, Merck, Silicagel 60) to obtain the titlecompound (22.67 g, 75.06 mmol) in a yield of 68%.

¹H NMR (CDCl₃): δ 7.92-7.75 (4H, m), 7.15-7.02 (3H, m), 3.87-3.81 (6H,d)

MW: 302

(2) Preparation of2-(4-fluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methylester

3-[(4-fluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester (10g, 34.48 mmol) obtained in step 1 was dissolved in 50% methanol and 5%NaOCl (61 ml, 41.38 mmol) was added dropwise thereto at roomtemperature. After 5 min, Na₂CO₃ (7.31 g, 68.96 mmol) was added dropwisethereto and refluxed for 5 min. The resulting solution was cooled toroom temperature, extracted with ethyl acetate, and the extract wasconcentrated under a reduced pressure. The resulting residue waspurified by silica gel column chromatography to obtain the titlecompound (5.66 g, 19.65 mmol) in a yield of 57%.

¹H NMR (CDCl₃): δ 8.18 (2H, t), 7.91 (1H, d), 7.30-7.25 (2H, t), 6.65(1H, d), 6.85 (1H, d), 4.08 (3H, s), 3.98 (3H, s)

MW: 300

(3) Preparation of2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

2-(4-fluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methylester (3 g, 10.00 mmol) obtained in step 2 was dissolved in toluene,aluminum chloride (6.67 g, 30.00 mmol) was added thereto and refluxedfor 8 hours. The resulting solution was cooled to room temperature, thereaction was stopped by adding 3 N HCl thereto and stirred for 30 min.The precipitate formed was filtered, washed with benzene and dried toobtain the title compound (1.96 g, 7.20 mmol) in a yield of 72%.

¹H NMR (MeOH-d₄): δ 8.19-8.15 (2H, t), 8.06 (1H, d), 7.50-7.44 (2H, t),7.00 (1H, d)

MW: 272

(4) Preparation of2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methylester

2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (500mg, 1.84 mmol) obtained in step 3 was dissolved in methanol, H₂SO₄ (0.49ml, 9.20 mmol) was added dropwise thereto and refluxed for 15 hours. Theresulting solution was cooled to room temperature, concentrated under areduced pressure to remove methanol, and the residue was neutralizedwith NaHCO₃. Then, the neutralized residue was extracted with ethylacetate and concentrated under a reduced pressure to obtain a residuewhich was purified by silica gel chromatography to obtain the titlecompound (397 mg, 1.39 mmol) in a yield of 76%.

¹H NMR (CH₃OH-d₄): δ 8.22-8.18 (2H, t), 7.80 (1H, d), 7.32-7.26 (2H, t),6.70 (1H, d), 3.97 (3H, s)

MW: 286

(5) Preparation of Wang Resin-Supported2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methylester

(4-bromomethylphenoxy)-methyl polystyrene Wang resin (476 mg, 0.67 mmol)was dissolved in DMF, and2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methylester (567 mg, 2.01 mmol) obtained in step 4, Cs₂CO₃ (655 mg, 2.01 mmol)and KI (334 mg, 2.01 mmol) were added thereto to be stirred at 50 to 60°C. for 12 hours. The resulting solution was cooled to room temperatureand filtered. The filtrate was washed with DMF, MeOH and CH₂Cl₂ anddried to obtain the title compound (608 mg, 0.65 mmol) in a yield of98%.

(6) Preparation of Wang Resin-Supported2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

Wang resin-supported2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methylester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF,LiOH.H₂O (99 mg, 2.35 mmol) in MeOH—H₂O (2:1) was added thereto and theresulting mixture was refluxed for 5 hours. The resulting solution wascooled to room temperature and filtered. The filtrate was washed withMeOH and CH₂Cl₂, and dried to obtain the title compound (551 mg, 0.42mmol) in a yield of 90%.

PREPARATION EXAMPLE 5 Preparation of Wang Resin-Supported2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid(R¹═F, R²═H and R³═F) (1) Preparation of3-[(2,4-difluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester

Anhydrous p-toluene sulfonic acid (25.0 g, 137.43 mmol) was melted at120° C. and 3-amino-4-methoxy benzoic acid methyl ester (10 g, 55.25mmol) obtained in step 1 of Preparation Example 1 and2,4-difluorobenzonitrile (11.53 g, 82.87 mol) were added thereto andstirred at 160° C. for 8 hours. The resulting solution was cooled toroom temperature and the reaction was stopped by adding NaHCO₃ thereto.The resulting mixture was extracted with ethyl acetate, the extract wasdried over MgSO₄ and concentrated under a reduced pressure. Theresulting residue was purified by silica gel column chromatography toobtain the title compound (10.0 g, 31.22 mmol) in a yield of 57%.

¹H NMR (CDCl₃): δ 8.31-8.22 (1H, m), 7.82-7.79 (1H, d), 7.65 (1H, s),7.02-6.85 (3H, m), 3.88 (6H, s)

MW: 320

(2) Preparation of2-(2,4-difluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acidmethyl ester

3-[(2,4-difluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester(9.5 g, 29.66 mmol) obtained in step 1 was dissolved in 50% methanol and5% NaOCl (53 ml, 35.71 mmol) was added dropwise thereto at roomtemperature. After 5 min, Na_(2l CO) ₃ (6.29 g, 59.34 mmol) was addeddropwise thereto and refluxed for 5 min. The resulting solution wascooled to room temperature, extracted with ethyl acetate, and theextract was concentrated under a reduced pressure. The resulting residuewas purified by silica gel column chromatography to obtain the titlecompound (3.50 g, 11.0 mmol) in a yield of 37%.

¹H NMR (CDCl₃): δ 10.99 (1H, bs). 8.65-8.57 (1H, m), 0.92 (1H, d),7.10-6.97 (2H, m), 6.76 (1H, d), 4.13 (3H, s), 4.00 (3H, s)

MW: 318

(3) Preparation of2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

2-(2,4-difluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acidmethyl ester (2.24 g, 7.04 mmol) obtained in step 2 was dissolved intoluene, aluminum chloride (3.75 g, 28.12 mmol) was added thereto andrefluxed for 8 hours. The resulting solution was cooled to roomtemperature, the reaction was stopped by adding 3 N HCl thereto andstirred for 30 min. The precipitate formed was filtered, washed withbenzene and dried to obtain the title compound (1.70 g, 5.86 mmol) in ayield of 83%.

¹H NMR (CH₃OH-d₄): δ 8.13-8.03 (2H, m), 7.47-7.33 (2H, m), 7.04 (1H, d)

MW: 290

(4) Preparation of2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acidmethyl ester

2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid(1.70 mg, 5.86 mmol) obtained in step 3 was dissolved in methanol, SOCl₂(8.2 ml, 112 mmol) was added dropwise thereto and refluxed for 15 hours.The resulting solution was cooled to room temperature, concentratedunder a reduced pressure to remove methanol, and the residue wasneutralized with NaHCO₃. Then, the neutralized residue was extractedwith ethyl acetate and concentrated under a reduced pressure to obtain aresidue which was purified by silica gel chromatography to obtain thetitle compound (1.50 mg, 1.64 mmol) in a yield of 84%.

¹H NMR (DMSO-d₆): δ 12.04 (1H, bs), 0.30-8.04 (1H, m), 7.73 (1H, d),7.55-7.48 (1H, m), 7.33-7.27 (1H, m), 6.70 (1H, d), 4.01 (3H, s)

MW: 304

(5) Preparation of Wang Resin-Supported2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acidmethyl ester

(4-bromomethylphenoxy)-methyl polystyrene Wang resin (476 mg, 0.67 mmol)was dissolved in DMF, and2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acidmethyl ester (567 mg, 2.01 mmol) obtained in step 4, Cs₂CO₃ (655 mg,2.01 mmol) and KI (334 mg, 2.01 mmol) were added thereto to be stirredat 50 to 60° C. for 12 hours. The resulting solution was cooled to roomtemperature and filtered. The filtrate was washed with DMF, MeOH andCH₂Cl₂ and dried to obtain the title compound (608 mg, 0.65 mmol) in ayield of 98%.

(6) Preparation of Wang Resin-Supported2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

Wang resin-supported2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acidmethyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved inTHF, LiOH.H₂O (99 mg, 2.35 mmol) in MeOH—H₂O was added thereto and theresulting mixture was refluxed for 5 hours. The resulting solution wascooled to room temperature and filtered. The filtrate was washed withMeOH and CH₂Cl₂, and dried to obtain the title compound (551 mg, 0.42mmol) in a yield of 90%.

PREPARATION EXAMPLE 6 Preparation of Wang Resin-Supported2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylicacid (R¹═Cl, R²═H and R³═F) (1) Preparation of3-[(2-chloro-4-fluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methylester

Anhydrous p-toluene sulfonic acid (41.99 g, 220.76 mmol) was melted at120° C. and 3-amino-4-methoxy benzoic acid methyl ester (20 g, 110.38mmol) obtained in step 1 of Preparation Example 1 and2-chloro-4-fluorobenzonitrile (25.76 g, 165.57 mol) were added theretoand stirred at 160° C. for 8 hours. The resulting solution was cooled toroom temperature and the reaction was stopped by adding NaHCO₃ thereto.The resulting mixture was extracted with ethyl acetate, the extract wasdried over MgSO₄ and concentrated under a reduced pressure. Theresulting residue was purified by silica gel column chromatography toobtain the title compound (26.70 g, 79.47 mmol) in a yield of 72%.

¹H NMR (CDCl₃): δ 7.92-7.75 (4H, m), 7.15-7.02 (3H, m), 3.87-3.81 (6H,d)

MW: 336

(2) Preparation of2-(2-chloro-4-fluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylicacid methyl ester

3-[(2-chloro-4-fluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methylester (10 g, 29.76 mmol) obtained in step 1 was dissolved in 50%methanol and 5% NaOCl (53 ml, 35.71 mmol) was added dropwise thereto atroom temperature. After 5 min, Na₂CO₃ (6.31 g, 59.52 mmol) was addeddropwise thereto and refluxed for 5 min. The resulting solution wascooled to room temperature, extracted with ethyl acetate, the extractwas concentrated under a reduced pressure. The resulting residue waspurified by silica gel column chromatography to obtain the titlecompound (5.17 g, 15.48 mmol) in a yield of 52%.

¹H NMR (CDCl₃): δ 8.18 (2H, t), 0.91 (1H, d), 7.30-7.25 (2H, t), 6.65(1H, d), 6.85 (1H, d), 4.08 (3H, s), 3.98 (3H, s)

MW: 334

(3) Preparation of2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylicacid

2-(2-chloro-4-fluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylicacid methyl ester (3 g, 8.98 mmol) obtained in step 2 was dissolved intoluene and aluminum chloride (5.99 g, 44.90 mmol) was added thereto,refluxed for 8 hours. The resulting solution was cooled to roomtemperature, the reaction was stopped by adding 3 N HCl thereto andstirred for 30 min. The precipitate formed was filtered, washed withbenzene and dried to obtain the title compound (1.87 g, 6.11 mmol) in ayield of 68%.

¹H NMR (CH₃OH-d₄): δ 8.19-8.15 (2H, t), 8.06 (1H, d), 7.50-7.44 (2H, t),7.00 (1H, d)

MW: 306

(4) Preparation of2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylicacid methyl ester

2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylicacid (500 mg, 1.63 mmol) obtained in step 3 was dissolved in methanol,H₂SO₄ (0.43 ml, 8.15 mmol) was added dropwise thereto and refluxed for15 hours. The resulting solution was cooled to room temperature,concentrated under a reduced pressure to remove methanol, and theresidue was neutralized with NaHCO₃. Then, the neutralized residue wasextracted with ethyl acetate and concentrated under a reduced pressureto obtain a residue which was purified by silica gel chromatography toobtain the title compound (393 mg, 1.23 mmol) in a yield of 67%.

¹H NMR (CH₃OH-d₄): δ 8.22-8.18 (2H, t), 7.80 (1H, d), 7.32-7.26 (2H, t),6.70 (1H, d), 3.97 (3H, s)

MW: 320

(5) Preparation of Wang Resin-Supported2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylicacid methyl ester

(4-bromomethylphenoxy)-methyl polystyrene Wang resin (476 mg, 0.67 mmol)was dissolved in DMF, and2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylicacid methyl ester (567 mg, 2.01 mmol) obtained in step 4, Cs₂CO₃ (655mg, 2.01 mmol) and KI (334 mg, 2.01 mmol) were added thereto to bestirred at 50 to 60° C. for 12 hours. The resulting solution was cooledto room temperature and filtered. The filtrate was washed with DMF, MeOHand CH₂Cl₂ and dried to obtain the title compound (608 mg, 0.65 mmol) ina yield of 98%.

(6) Preparation of Wang Resin-Supported2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylicacid

Wang resin-supported2-(2-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylicacid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolvedin THF, LiOH.H₂O (99 mg, 2.35 mmol) in MeOH—H₂O was added thereto andthe resulting mixture was refluxed for 5 hours. The resulting solutionwas cooled to room temperature and filtered. The filtrate was washedwith MeOH and CH₂Cl₂, and dried to obtain the title compound (551 mg,0.42 mmol) in a yield of 90%.

PREPARATION EXAMPLE 7 Preparation of Wang Resin-Supported2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylicacid (R¹═H, R²═Cl and R³═F) (1) Preparation of3-[(3-chloro-4-fluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methylester

Anhydrous p-toluene sulfonic acid (10 g, 52.57 mmol) was melted at 120°C. and 3-amino-4-methoxy benzoic acid methyl ester (3.88 g, 21.44 mmol)obtained in step 1 of Preparation Example 1 and3-chloro-4-fluorobenzonitrile (5.0 g, 32.14 mol) were added thereto andstirred at 160° C. for 8 hours. The resulting solution was cooled toroom temperature and the reaction was stopped by adding NaHCO₃ thereto.The resulting mixture was extracted with ethyl acetate, the extract wasdried over MgSO₄ and concentrated under a reduced pressure. Theresulting residue was purified by silica gel column chromatography toobtain the title compound (3.24 g, 9.62 mmol) in a yield of 45%.

¹H NMR (CDCl₃): δ 7.96-7.95 (1H, m), 7.76-7.73 (2H, m), 7.60 (1H, bs),7.17-7.11 (1H, m), 6.93(1H, d), 3.85(3H, s), 3.84 (3H, d)

MW: 336

(2) Preparation of2-(3-chloro-4-fluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylicacid methyl ester

3-[(3-chloro-4-fluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methylester (3.24 g, 9.62 mmol) was dissolved in 50% methanol and 5% NaOCl (18ml, 11.90 mmol) was added dropwise thereto at room temperature. After 5min, Na₂CO₃ (2.04 g, 19.25 mmol) was added dropwise thereto and refluxedfor 5 min. The resulting solution was cooled to room temperature,extracted with ethyl acetate, and the extract was concentrated under areduced pressure. The resulting residue was purified by silica gelcolumn chromatography to obtain the title compound (0.95 g, 2.83 mmol)in a yield of 30%.

¹H NMR (CDCl₃): δ 10.68 (1H, bs), 8.23-8.20 (1H, m), 7.96-7.91 (1H, m),7.87 (1H, d), 7.27-7.20 (1H, m), 6.73 (1H, d), 4.10 (3H, s), 3.97 (3H,s)

MW: 334

(3) Preparation of2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylicacid

2-(3-chloro-4-fluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylicacid methyl ester (0.95 g, 8.98 mmol) obtained in step 2 was dissolvedin toluene, aluminum chloride (1.5 g, 11.25 mmol) was added thereto andrefluxed for 8 hours. The resulting solution was cooled to roomtemperature, the reaction was stopped by adding 3 N HCl thereto andstirred for 30 min. The precipitate formed was filtered, washed withbenzene and dried to obtain the title compound (0.81 g, 2.64 mmol) in ayield of 80%.

¹H NMR (MeOH-d₄): δ 8.34 (1H, dd), 8.22-8.08 (2H, m), 7.62 (1H, t), 7.03(1H, d)

MW: 306

(4) Preparation of2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylicacid methyl ester

2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylicacid (800 mg, 2.64 mmol) obtained in step 3 was dissolved in methanol,SOCl₂ (1.93 ml, 26.41 mmol) was added dropwise thereto and refluxed for15 hours. The resulting solution was cooled to room temperature,concentrated under a reduced pressure to remove methanol, and theresidue was neutralized with NaHCO₃. Then, the neutralized residue wasextracted with ethyl acetate and concentrated under a reduced pressureto obtain a residue which was purified by silica gel chromatography toobtain the title compound (690 mg, 2.15 mmol) in a yield of 81%.

¹H NMR (DMSO-d₆): δ 12.39 (1H, bs), 8.56 (1H, d), 8.30 (1H, bs), 7.72(1H, d), 7.59 (1H, t), 6.69 (1H, d), 3.90 (3H, s)

MW: 320

(5) Preparation of Wang Resin-Supported2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylicacid methyl ester

(4-bromomethylphenoxy)-methyl polystyrene Wang resin (476 mg, 0.67 mmol)was dissolved in DMF, and2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylicacid methyl ester (567 mg, 2.01 mmol) obtained in step 4, Cs₂CO₃ (655mg, 2.01 mmol) and KI (334 mg, 2.01 mmol) were added thereto to bestirred at 50 to 60° C. for 12 hours. The resulting solution was cooledto room temperature and filtered. The filtrate was washed with DMF, MeOHand CH₂Cl₂ and dried to obtain the title compound (608 mg, 0.65 mmol) ina yield of 98%.

(6) Preparation of Wang Resin-Supported2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylicacid

Wang resin-supported2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylicacid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolvedin THF, LiOH.H₂O (99 mg, 2.35 mmol) in MeOH—H₂O was added thereto andthe resulting mixture was refluxed for 5 hours. The resulting solutionwas cooled to room temperature and filtered. The filtrate was washedwith MeOH and CH₂Cl₂, and dried to obtain the title compound (551 mg,0.42 mmol) in a yield of 90%.

EXAMPLE 1 Preparation of7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid amide(R⁴R⁵NH₂═NH₄Cl)

Wang resin-supported 7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylicacid (36 mg, 0.03 mmol) obtained in Preparation Example 1 was dissolvedin 3 ml of DMF and aluminum chloride (5 mg, 0.09 mmol), EDCI (18 mg,0.09 mmol), DMAP (11 mg, 0.09 mmol) and HOBt (12 mg, 0.09 mmol) wereadded thereto and the resulting mixture was stirred at room temperature.The resulting solution was filtered, the filtrate was washed with DMF,MeOH and CH₂Cl₂ and dried to obtain Wang resin-supported7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid amide.

Then, 30 mg of Wang resin-supported7-hydroxy-2-phenyl-1H-benzoimidazole-4-carboxylic acid amide wasdissolved in 0.2 ml of CH₂Cl₂, 0.2 ml of trifluoroacetic acid was addedthereto and stirred for 30 min. The resulting solution was filtered, thefiltrate was washed with MeOH and CH₂Cl₂ and dried to obtain the titlecompound in a yield of 90%.

¹H NMR (CH₃OH-d₄): δ 8.15 (2H, d), 7.84 (1H, d), 7.78-7.56 (3H, m), 6.83(1H, m)

MW: 253

EXAMPLE 2 TO 203

The same procedure as described in Example 1 was repeated using R⁴R⁵NH₂listed in Table 2 to obtain the compounds 2 to 203, respectively. TABLE2 Com Pre No. No. Chemical compound R⁴N(CH₂)_(n)R⁵ n ¹H NMR(CH₃OH-d₄) MW 2 1 7-hydroxy-2-phenyl-1H-benzo- aniline 0 δ 8.10(2H, d), 7.87(1H, d),7.85-7.60(3H, m), 329 imidazole-4-carboxylic 7.40(2H, d), 07.39-7.28(2H,m), 7.27-7.20(1H, acid-phenylamide m), 6.89(1H, d)  3 17-hydroxy-2-phenyl-1H- 4-hydroxyaniline 0 δ 8.28-8.03(3H, m),7.98-7.82(1H, d), 345 benzoimidazole-4-carboxylic 7.79-7.56(3H, m),7.48(2H, d), 6.85-6.72(2H, m) acid(4-hydroxy-phenyl)-amide  4 17-hydroxy-2-phenyl-1H- 1,4-diaminophenylene 0 δ 8.28-8.14(2H, m),8.03-7.91(3H, m), 344 benzoimidazole-4-carboxylic 7.71-7.56(3H, m),7.46-7.34(2H, d), acid(4-amino-phenyl)-amide 6.89-6.76(1H, d)  5 17-hydroxy-2-phenyl-1H- 4-hydroxycyclohexylamine 0 δ 8.08(2H, d),7.82(1H, d), 7.78-7.50(3H, m), 351 benzoimidazole-4-carboxylic 6.88(1H,d), 4.15-3.82(1H, m), 3.70-3.54(1H, acid(4-hydroxy-cyclohexyl)- m),2.30-1.90(4H, m), 1.85-1.20(4H, m) amide  6 1 7-hydroxy-2-phenyl-1H-4-(hydroxymethyl)aniline 0 δ 8.20(2H, d), 7.92(2H, d), 7.81-7.70(1H, m),359 benzoimidazole-4-carboxylic 7.69-7.58(3H, m), 7.50-7.30(1H, m),acid(4-hydroxymethyl-phenyl)- 7.29-7.10(1H, m), 6.89(1H, d), 4.65(2H, s)amide  7 1 7-hydroxy-2-phenyl-1H- 4-(hydroxyethyl)aniline 0 δ 8.14(2H,d), 7.98(1H, d), 7.78-7.60(5H, m), 373 benzoimidazole-4-carboxylic7.30-7.18(2H, m), 6.88(1H, d), 4.65(1H, t), acid[4-(2-hydroxy-ethyl)-3.73(1H, t), 3.02(1H, t), 2.81(1H, t) phenyl]-amine  8 17-hydroxy-2-phenyl-1H- 4-(aminoethyl)aniline 0 δ 8.27-8.16(2H, m),7.95(1H, d), 7.78(2H, d), 372 benzoimidazole-4-carboxylic 7.66-7.54(3H,m), 7.44(2H, d), 6.86(1H, d), acid[4-(2-amino-ethyl)-phenyl]- 3.19(2H,t), 2.92(2H, t) amide  9 1 7-hydroxy-2-phenyl-1H- N-[2-(4-amino-phenyl)-0 δ 8.20-8.02(3H, m), 8.00(2H, d), 7.70-7.68(5H, 526benzoimidazole-4-carboxylic ethyl]-4-methylbenzene- m), 7.38(2H, d),7.16(2H, d), 6.94(1H, d), acid{4-[2-(toluene-4-sulfonyl- sulfonamide3.10(2H, t), 2.73(2H, t), 2.43(3H, s) amino)-ethyl]-phenyl}-amide  10 17-hydroxy-2-phenyl-1H- N-[2-(4-amino-phenyl)- 0 δ 8.13(2H, d), 7.98(1H,d), 7.75-7.53(5H, m), 450 benzoimidazole-4-carboxylic ethyl]-4-methane-7.29(2H,d), 6.91(1H, d), 3.30(2H, t), 2.82(2H, t)acid[4-(2-methanesulfonyl- sulfonamide amino-ethyl)-phenyl]-amide  11 17-hydroxy-2-phenyl-1H- 2-[2-(4-aminophenyl)- 0 δ 7.45(2H, d),6.98-6.84(4H, m), 6.82(2H, d), 502 benzoimidazole-4-carboxylic-ethyl]-isoindole-1,3-dione 6.73-6.54(4H, m), 6.30(2H, d), 5.89(1H, d),acid{4-[2-(1,3-dioxo-1,3- 2.91(2H, t), 2.00(2H, t)dihydro-isoindole-2-yl)-ethyl]- phenyl}-amide  12 17-hydroxy-2-phenyl-1H- thiophene-2-sulfonic acid 0 δ 8.15(2H, d),8.06(1H, d), 7.80-7.55(7H, m), 518 benzoimidazole-4-carboxylic[2-(4-amino-phenyl)- 7.23-7.10(3H, m), 7.05(1H, d), 3.16(2H, t),acid{4-[2-(thiophene-2- ethyl]-amide 2.80(2H, t)sulfonylamino)-ethyl]-phenyl}- amide  13 1 7-hydroxy-2-phenyl-1H-N-[2-(4-amino-phenyl)- 0 δ 8.17(2H, d), 8.03(1H, d), 7.77-7.68(5H, m),464 benzoimidazole-4-carboxylic ethyl]-ethanesulfonamide 7.27(2H, d),7.01(1H, d), 3.31(2H, t), 2.99(2H, acid[4-(2-ethanesulfonylamino- q),2.85(2H, t), 1.23(3H, t) ethyl)-phenyl]-amide  14 22-(4-chloro-phenyl)-7-hydroxy- aniline 0 δ 8.18(2H, d), 8.11(1H, d),7.80(2H, d), 7.67(2H, 363 1H-benzoimidazole-4-carboxylic d), 7.40(2H,t), 7.15(1H, t), 6.89(1H, d) acid phenylamide  15 22-(4-chloro-phenyl)-7-hydroxy- 4-hydroxycyclo- 0 δ 8.15(2H, d), 7,84(1H,d), 7.69(2H, d), 6.90(1H, 385 1H-benzoimidazole-4-carboxylic hexylamined), 3.95(1H, m), 3.58(1H, m), 2.28-1.95(4H, m),acid(4-hydroycyclohexyl)-amide 1.83-1.25(4H, m)  16 22-(4-chloro-phenyl)-7-hydroxy- N-[2-(4-amino-phenyl)- 0 δ 8.18(2H, d),7.98(1H, d), 7.80-7.60(6H, m), 560 1H-benzoimidazole-4-carboxylicethyl]-4-methyl- 7.36(2H, d), 7.16(2H, d), 6.94(1H, d), 3.09(2H,acid{4-[2-(toluene-4-sulfonyl- benzenesulfonamide t), 2.74(2H, t),2.41(3H, s) amino)-ethyl]-phenyl}-amide  17 22-(4-chloro-phenyl)-7-hydroxy- N-[2-(4-amino-phenyl)- 0 δ 8.15(1H, d),7.94(1H, d), 7.72(2H, d), 7.62(2H, 484 1H-benzoimidazole-4-carboxylicethyl]-methenesulfonyl- d), 7.28(2H, d), 6.85(1H, d), 3.32(2H, t),acid[4-(2-methanesulfonyl- amide 2.85(3H, s), 2.84(2H, t)amino-ethyl)-phenyl]-amide  18 2 2-(4-chloro-phenyl-7-hydroxy-2-[2-(4-amino-phenyl)- 0 δ 8.16(2H, d), 8.02(1H, d), 7.86-7.76(4H, m),536 1H-benzoimidazole-4-carboxylic ethyl]-isoindole-1,3-dione7.75-7.61(4H, m), 7.22(2H, d), 6.95(1H, m), acid{4-[2-(1,3-dioxo-1,3-3.90(2H, t), 2.97(2H, t) dihydro-isoindole-2-yl)-ethyl]- phenyl}-amide 19 2 2-(4-chloro-phenyl)-7-hydroxy- thiophene-2-sulfonic 0 δ 8.15(2H,d), 7.97(2H, d), 7.75-7.57(6H, m), 552 1H-benzoimidazole-4-carboxylicacid[2-(4-amino-phenyl)- 7.19(2H, d), 6.92(1H, d), 3.17(2H, t), 2.77(2H,t) acid{4-[2-(thiophene-2-sulfonyl- ethyl]-amideamino-ethyl)-phenyl]-amide  20 2 2-(4-chloro-phenyl)-7-hydroxy-N-[2-(4-amino-phenyl)- 0 δ 8.17(2H, d), 8.09(2H, d), 7.73(2H, d),7.63(2H, 498 1H-benzoimidazole-4-carboxylic ethyl]-ethanesulfonylamided), 7.29(2H, d), 3.31(2H, t), 2.98(2H, q),acid[4-(2-ethanesulfonylamino- 2.85(2H, t), 1.24(3H, t)ethyl)-phenyl]-amide  21 3 2-(2,4-dichloro-phenyl)-7- ammonium chloride0 δ 7.98-7.70(2H, m), 7.69-7.52(1H, m), 321 hydroxy-1H-benzoimidazole-4-7.28-7.00(1H, m), 6.95-6.82(1H, m) carboxylic acid phenylamide  22 32-(2,4-dichloro-phenyl)-7- aniline 0 δ 8.02(1H, d), 8.01-7.82(1H, m),7.81-7.65(3H, 397 hydroxy-1H-benzoimidazole-4- m), 7.64-7.45(1H, m),7.43-7.20(2H, t), carboxylic acid phenylamide 7.42-7.02(1H, t), 6.90(1H,d)  23 3 2-(2,4-dichloro-phenyl)-7- 4-hydroxy-cyclohexyl- 0 δ8.02-7.68(2H, m), 7.68-7.48(1H, m), 419 hydroxy-1H-benzoimidazole-4-amine 7.20-7.03(1H, m), 6.88(1H, d), 3.93(1H, m), carboxylicacid(4-hydroxy- 3.58(1H, m), 2.25-1.85(4H, m), cyclohexyl)-amide1.84-1.39(4H, m)  24 3 2-(2,4-dichloro-phenyl)-7- 4-aminophenethylamine0 δ 7.97(2H, d), 7.85-7.63(3H, m), 7.56(1H, d), 440hydroxy-1H-benzoimidazole-4- 7.38-7.20(2H, m), 6.82(1H, d), 3.18(2H, t),carboxylic acid[4-(2-amino- 2.96(2H, t) ethyl)-phenyl]-amide  25 32-(2,4-Dichloro-phenyl)-7- 1,4-phenylenediamine 0 δ 8.06-7.81(4H, m),7.80-7.64(1H, s), 7.58(1H, 412 hydroxy-1H-benzoimidazole-4- d), 7,38(2H,d), 6.84(1H, d) carboxylic acid(4-amino- phenyl)-amide  26 32-(2,4-Dichloro-phenyl)-7- 4-aminobenzy alcohol 0 δ 8.00(1H, d),7.98-7.84(1H, m), 7.75(1H, m), 427 hydroxy-1H-benzoimidazole-4-7.74-7.52(2H, m), 7.50-7.26(1H, m), carboxylic acid(4-hydroxy-7.25-7.05(2H, m), 7.04-6.80(1H, m) methyl-phenyl)-amide  27 32-(2,4-Dichloro-phenyl)-7- 4-aminophenethyl alcohol 0 δ 8.15-7.86(2H,m), 7.85-7.45(3H, m), 7.25(2H, 441 hydroxy-1H-benzoimidazole-4- d),7.20-6.75(2H, m), 4.58(1H, t), 3.75(1H, t), carboxylicacid[4-(2-hydroxy- 3.05(1H, t), 2.81(1H, t) ethyl)-phenyl]-amide  28 32-(2,4-dichloro-phenyl)-7- N-[2-(4-amino-phenyl)- 0 δ 8.20-8.02(3H, m),8.00(2H, d), 7.70-7.68(3H, 594 hydroxy-1H-benzoimidizaole-4-ethyl]-4-methyl-benzene- m), 7.38(2H, d), 7.16(2H, d), 6.94(1H, d),carboxylic acid{4-[2-(toluene- sulfonamide 3.10(2H, t), 2.73(2H, t),2.43(3H, s) 4-sulfonylamino)-ethyl]- phenyl}-amide  29 32-(2,4-dichloro-phenyl)-7- N-[2(4-amino-phenyl)- 0 δ 8.02(1H, d),8.01-7.78(1H, m), 7.70(2H, d), 518 hydroxy-1H-benzoimidazole-4-ethyl]-methanesulfonamide 7.67-7.50(1H, m), 7.25(2H, d), 6.90(2H, d),carboxylic acid[4-(2-methane- 3.28(2H, t), 2.84(2H, t), 2.82(3H, s)sulfonylamino-ethyl)-phenyl]- amide  30 3 2-(2,4-dichloro-phenyl)-7-2-[2-(4-amino-phenyl)- 0 δ 7.10(1H, d), 6.99-6.81(6H, m), 6.80-6.65(3H,570 hydroxy-1H-benzoimidazole-4- ethyl]-isoindole-1,3-dione m), 6.28(2H,d), 5.92(1H, d), 2.88(2H, t), carboxylic acid{4-[2-(1,3- 1.97(2H, t)dioxo-1,3-dihydro-isoindole-2- yl)-ethyl]-phenyl}-amide  31 32-(2,4-dichloro-phenyl)-7- thiophene-2-sulfonic 0 δ 8.08(1H, d),7.88(2H, m), 7.83(1H, d), 586 hydroxy-1H-benzoimidazole-4-acid[2-(4-amino-phenyl)- 7.75(1H, d), 7.68-7.65(3H, m), 7.63(1H, d),carboxylic acid{4-[2-(thiophene- ethyl]-amide 7.17-7.01(2H, m), 6.97(1H,d), 3.16(2H, t), 2-sulfonylamino)-ethyl]- 2.77(2H, t) phenyl}-amide  323 2-(2,4-dichloro-phenyl)-7- N-[2-(4-amino-phenyl)- 0 δ 8.11(1H, d),7.95-7.82(2H, m), 7.75-7.60(3H, 532 hydrioxy-1H-benzoimidazole-4-ethyl]-ethanesulfonamide m), 7.28(2H, d), 7.01(1H, d), 3.31(2H, t),carboxylic acid[4-(2-ethane- 2.98(2H, q), 2.85(2H, t), 1.24(3H, t)sulfonylamino-ethyl)-phenyl]- amide  33 4 2-(4-fluoro-phenyl)-7-hydroxy-N-[2-(4-amino-phenyl)- 0 δ 8.23-8.15(2H, m), 7.91(1H, d), 7.69(2H, d),1H-benzoimidazole-4-carboxylic ethyl]-methanesulfonamide 7.39(2H, t),7.26(2H, d), 6.83(1H, d), 3.31(2H, t), acid[4-(2-methanesulfonyl-2.85-2.78(5H, m) amino-ethyl)-phenyl]-amide  34 42-(4-fluoro-phenyl)-7-hydroxy- N-[2-(4-amino-phenyl)- 0 δ 8.25-8.21(2H,m), 7.98-7.93(2H, m), 1H-benzoimidazole-4-carboxylic ethyl]-4-methyl-7.71-7.64(4H, m), 7.41-7.34(3H, m), 7.14(2H,acid{4-[2-(toluene-4-sulfonyl- benzenesulfonamide d), 6.87(1H, d),3.08(2H, t), 2.73(2H, t), amino)-ethyl]-amide 2.40(3H, s)  35 42-(4-fluoro-phenyl)-7-hydroxy- N-[2-(4-amino-phenyl)- 0 δ 8.05(2H, t),7.78(1H, d), 7.30(2H, t), 7.14(2H, 1H-benzoimidazole-4-carboxylicethyl]-ethanesulfonamide d), 6.77(2H, d), 6.69(1H, d), 3.78(2H, q),acid[4-(2-methanesulfonyl- 3.35(2H, t), 2.90(2H, t), 1.28(3H, t)amino-ethyl)-phenyl]-amide  36 4 2-(4-fluoro-phenyl)-7-hydroxy-4-morpholin-4-yl- 0 1H-benzoimidazole-4-carboxylic phenylamineacid(4-morpholin-4-yl-phenyl)- amide  37 5 2-(2,4-difluoro-phenyl)-7-N-[2-(4-amino-phenyl)- 0 δ 7.90(1H, d), 7.62(1H, d), 7.31-7.17(4H, m),hydroxy-1H-benzoimidazole-4- ethyl]-methanesulfonamide 6.81(1H, d),3.22(2H, t), 2.76(5H, m) carboxylic acid[4-(2-methane-sulfonylamino-ethyl)-phenyl]- amide  38 5 2-(2,4-difluoro-phenyl)-7-N-[2-(4-amino-phenyl)- 0 δ 7.99(1H, m), 7.74(1H, d), 7.50(2H, d),hydroxy-1H-benzoimidazole-4- ethyl]-4-methyl-benzene- 7.33-7.26(2H, m),7.23(4H, m), 6.94(2H, d), carboxylic acid {4-[2-(toluene- sulfonamide6.81(1H, d), 3.58(2H, t), 2.82(2H, t), 2.23(3H, s)4-sulfonylamino)-ethyl]- phenyl}amide  39 5 2-(2,4-difluoro-phenyl)-7-N-[2-(4-amino-phenyl)- 0 δ 8.19-8.00(2H, m), 7.70(1H, d), 7.43-7.26(4H,hydroxy-1H-benzoimidazole-4- ethyl]-ethanesulfonamide m), 6.87(1H, d),3.98(2H, t), 2.97(2H, q), carboxylic acid[4-(2-methane- 2.86(2H, t),1.25(3H, t) sulfonylamino-ethyl)-phenyl]- amide  40 62-(2-chloro-4-fluoro-phenyl)- N-[2-(4-amino-phenyl)- 0 δ 8.01-7.93(1H,m), 7.65(3H, t), 7.53-7.44(2H, 7-hydroxy-1H-benzoimidazole-ethyl]-4-methyl-benzene- m), 7.33(4H, m), 7.11(2H, d), 6.80(1H, d),4-carboxylic acid{4-[2- sulfonamide) 3.09(2H, t), 2.72(2H, t), 2.38(3H,s) (toluene-4-sulfonylamino)- ethyl]-phenyl}amide  41 62-(2-chloro-4-fluoro-phenyl)- N-[2-(4-amino-phenyl)- 0 δ 8.06(1H, m),7.97(1H, d), 7.68-7.61(3H, m), 7-hydroxy-1H-benzoimidazole-ethyl]-methanesulfonamide 7.40(1H, m), 7.27(2H, m), 6.97(1H, m),3.61(2H, 4-carboxylic acid[4-(2- t), 2.84(5H, m)methanesulfonylamino-ethyl)- phenyl]-amide  42 62-(2-chloro-4-fluoro-phenyl)- N-[2-(4-amino-phenyl)- 0 δ 8.07(1H, m),7.97(1H, d), 7.68-7.40(3H, 7-hydroxy-1H-benzoimidazole-ethyl]ethanesulfonamide m), 7.28-7.18(3H, m), 6.99(1H, d), 3.61(2H, t),4-carboxylic acid[4-(2- 2.96(2H, q), 2.84(2H, t), 1.28(3H, t)methanesulfonylamino-ethyl)- phenyl]-amide  43 72-(3-chloro-4-fluoro-phenyl)- N-[2-(4-amino-phenyl)- 0 δ 8.18(1H, d),7.90(1H, m), 7.72(1H, d), 7-hydroxy-1H-benzoimidazole-ethyl]-4-methyl-benzene- 7.47(2H, d), 7.39(1H, m), 7.13-7.06(4H, m),4-carboxylic acid{4-[2- sulfonamide 6.95(2H, d), 6.75(1H, d), 3.63(2H,t), 2.85(2H, t), (toluene-4-sulfonylamino)- 2.23(3H, s)ethyl]-phenyl}amide  44 7 2-(3-chloro-4-fluoro-phenyl)-N-[2-(4-amino-phenyl)- 0 δ 8.27(1H, d), 8.10(1H, m), 7.85(1H, d),7-hydroxy-1H-benzoimidazole- ethyl]-ethanesulfonamide 7.64(2H, d),7.41(1H, t), 7.22(2H, d), 6.76(1H, 4-carboxylic acid{4-[2- d), 3.26(2H,t), 2.94(2H, q), 2.80(2H, t), methanesulfonylamino)- 1.22(3H, t)ethyl)-phenyl]amide  45 7 2-(3-chloro-4-fluoro-phenyl)-N-[2-(4-amino-phenyl)- 0 δ 8.31(1H, d), 8.12(1H, m), 7.91(1H, d),7-hydroxy-1H-benzoimidazole- ethyl]-methanesulfonamide 7.68(2H, d),7.47(1H, t), 7.26(2H, d), 6.83(1H, 4-carboxylic acid[4-(2- d), 3.31(2H,t), 2.85(5H, m) methanesulfonylamino-ethyl)- phenyl]-amide  46 1cyclohexyl-(7-hydroxy-2- piperidine 0 δ 7.31-7.23(5H, m), 7.05(1H, d),6.64(1H, d), 320 phenyl-1H-benzoimidazole-4- 3.53-3.29(4H, m),1.82-1.41(6H, m) yl)-methanone  47 2 2-(4-chloro-phenyl)-7-hydroxy-piperidine 0 δ 8.10(2H, d), 7.88(1H, d), 7.66(2H, d), 6.92(1H, 3551H-benzoimidazole-4-carboxylic d), 3.53-3.29(4H, m), 1.82-1.41(6H, m)acid cyclohexyl-amide  48 3 2-(2,4-dichloro-phenyl)-7- piperidine 0 δ7.31-7.23(3H, m), 7.05(1H, d), 6.64(1H, d), 389hydroxy-1H-benzoimidazole-4- 3.53-3.29(4H, m), 1.82-1.41(6H, m)yl-piperidine-1-yl-methanone  49 1 7-hydroxy-2-phenyl-1H-benzo-4-nitrobenzylamine- 1 δ 8.20(2H, d), 8.13(2H, d), 7.82(1H, d), 388imidazole-4-carboxylic acid(4- hydrochloride) 7.82-7.55(5H, m), 6.87(1H,d), 4.75(2H, s) nitro-benzyl)-amide  50 1 7-hydroxy-2-phenyl-1H-benzo-4-aminobenzylamine- 1 δ 8.15(2H, d), 7.82(1H, d), 7.72-7.52(5H, m), 358imidazole-4-carboxylic acid dihydro chloride 7.33(2H, d), 6.87(1H, d),4.70(2H, s) (4-amino-benzyl)-amide  51 1 7-hydroxy-2-phenyl-1H-benzo-benzylamine 1 δ 8.10(2H, d), 7.87(1H, d), 7.85-7.60(3H, m), 343imidazole-4-carboxylic acid 7.40(2H, d), 7.39-7.28(2H, m), 7.27-7.20(1H,benzylamide m), 6.89(1H, d), 4.66(2H, s)  52 22-(4-chloro-phenyl)-7-hydroxy- benzylamine 1 δ 8.10(2H, d), 7.88(1H, d),7.66(2H, d), 377 1H-benzoimidazole-4-carboxylic 7.42-7.23(5H, m),6.92(1H, d), 4.68(2H, s) acid benzylamide  53 22-(4-chloro-phenyl)-7-hydroxy- 4-nitrobenzylamine- 1 δ 8.20(2H, d),7.90(2H, d), 7.88(1H, s), 422 1H-benzoimidazole-4-carboxylichydrochloride 7.69-7.51(4H, m), 6.91(1H, d), 4.76(2H, s)acid(4-nitro-benzyl)-amide  54 2 2-(4-chloro-phenyl)-7-hydroxy-4-aminobenzylamine- 1 δ 8.20(2H, d), 7.90(2H, d), 7.88(1H, s), 3921H-benzoimidazole-4-carboxylic hydroxy chloride 7.69-7.51(4H, m),6.91(1H, d), 4.76(2H, s) acid(4-amino-benzyl)-amide  55 32-(2,4-dichloro-phenyl)-7- benzylamine 1 δ 8.10(2H, d), 7.88(1H, d),7.66(2H, d), 411 hydroxy-1H-benzoimidazole-4- 7.37-7.23(4H, m), 6.92(1H,d), 4.68(2H, s) carboxylic acid benzylamide  56 32-(2,4-Dichloro-phenyl)-7- 4-nitrobenzylamine 1 δ 8.20(2H, d), 7.90(2H,t), 7.88(1H, s), 456 hydroxy-1H-benzoimidazole-4- 7.69-7.51(3H, m),6.91(1H, d), 4.76(2H, s) carboxylic acid(4-nitro- benzyl)-amide  57 17-hydroxy-2-phenyl-1H-benzo- phenethylamine 2 δ 8.10(2H, d), 7.78(1H,d), 7.77-7.58(3H, m), 357 imidazole-4-carboxylic acid- 7.44-7.18(5H, m),6.85(1H, s), 3.68(2H, t), phenethyl-amide 2.98(2H, t)  58 17-hydroxy-2-phenyl-1H-benzo- 4-hydroxyphenethylamine 2 δ 8.02-7.92(2H,m), 7.77(1H, d), 7.62-7.42(3H, 373 imidazole-4-carboxylic acid(4- m),7.11(2H, d), 6.78(1H, d), 6.70(2H, d), hydroxy-pheneethyl)-amide3.72(2H, t), 2.83(2H, t)  59 1 7-hydroxy-2-phenyl-1H-benzo-4-nitrophenethylamine 2 δ 8.10(2H, d), 8.01(2H, d), 7.75(1H, d), 402imidazole-4-carboxylic acid(4- 7.69-7.52(3H, m), 7.50(2H, d), 6.85(1H,d), nitro-phenethyl)-amide 3.75(2H, t), 3.08(2H, t)  60 17-hydroxy-2-phenyl-1H-benzo- 4-aminophenethylamine 2 δ 8.11(2H, d),7.78(1H, d), 7.74-7.59(3H, m), 372 imidazole-3-carboxylic acid(4-7.46(2H, d), 7.31(2H, d), 6.85(1H, d), 3.72(2H, amino-phenethyl)-aminot), 3.02(2H, t)  61 1 7-hydroxy-2-phenyl-1H-benzo- ethylenediamine 2 δ7.95-7.70(2H, m), 7.69(1H, d), 7.60-7.42(1H, 296 imidazole-3-carboxylicacid(2- m), 7.41-7.23(2H, m), 3.77(2H, t), 3.25(2H, t)amino-ethyl)-amide  62 1 7-hydroxy-2-phenyl-1H-benzo-4-hydroxy-3-methoxy- 2 δ 8.10-8.00(2H, m), 7.78(1H, d), 7.69-7.52(3H,403 imidazole-3-carboxylic acid(4- phenethylamine m), 6.91-6.77(2H, m),6.72(2H, d), 3.73(3H, s), hydroxy-3-methoxy-phenethyl)- 3.70(2H, t),2.89(2H, t) amide  63 1 7-hydroxy-2-phenyl-1H-benzo-3-hydroxy-4-methoxy- 2 δ 8.08-7.93(2H, m), 7.78(1H, d), 7.62-7.50(2H,403 imidazole-4-carboxylic acid(3- phenethylamine m), 6.98-6.52(5H, m),3.80(3H, s), 3.68(2H, t), hydroxy-4-methoxy-phenethyl)- 2.82(2H, t)amide  64 1 7-hydroxy-2-phenyl-1H-benzo- N-[4-(2-amino-ethyl)- 2 δ8.07(1H, d), 7.77(1H, d), 7.65-7.61(4H, m), 450 imidazole-4-carboxylicacid[2- phenyl]-methane- 7.28(2H, d), 7.18(2H, d), 6.85(1H, d), 3.71(2H,(4-methanesulfonylamino- sulfonamide t), 2.95(2H, t), 2.85(3H, s)phenyl)-ethyl]-amide  65 1 7-hydroxy-2-phenyl-1H-benzo-N-[4-(2-amino-ethyl)- 2 δ 8.09(2H, d), 7.76-7.54(5H, m), 7.33-7.30(3H,526 imidazole-4-carboxylic acid{2- phenyl]-4-methyl- m), 7.20-7.13(2H,m), 7.01-6.87(3H, m), [4-(toluene-4-sulfonylamino)- benzenesulfonamide3.73(1H, t), 3.63(1H, t), 3.01(1H, t), 2.88(1H, phenyl]-ethyl}-amide t),2.44(3H, s)  66 1 7-hydroxy-2-phenyl-H-benzo- 4-(2-aminoethyl)- 2 δ8.17-8.12(2H, m), 7.88(1H, d), 7.77-7.71(3H, 366 imidazole-4-carboxylicacid(2- morpholine m), 7.00-6.95(1H, m), 4.02-3.75(4H, m),morpholin-4-yl-ethyl)-amide 3.89(2H, t), 3.47(2H, t), 3.46-3.00(4H, t) 67 1 7-hydroxy-2-phenyl-1H-benzo- 2-[4-(2-amino-ethyl)- 2 δ 8.14(2H,d), 7.97-7.68(8H, m), 7.40(4H, dd), 502 imidazole-4-carboxylic acid{2-phenyl]-isoindole-1,3-dione 6.93(1H, d), 3.74(2H, t), 3.05(2H, t)[4-(1,3-dioxo-1,3-dihydro-iso- indole-2-yl)-phenyl]-ethyl}- amide  68 17-hydroxy-2-phenyl-1H-benzo- N-[4-(2-amino-ethyl)- 2 δ 8.15(2H, d),7.79-7.72(4H, m), 7.22(4H, dd), imidazole-4-carboxylic acid[2-phenyl]-ethanesulfomamide 6.97(1H, d), 3.66(2H, t), 2.99(2H, q),2.89(2H, t), (4-ethanesulfonylamino-phenyl)- 1.22(3H, t) ethyl]-amide 69 1 7-hydroxy-2-phenyl-1H-benzo- 2-(2-aminoethylamino)-5- 2 δ 8.84(1H,d), 8.13-8.05(3H, m), 7.80-7.65(4H, 418 imidazole-4-carboxylic acid(5-nitropyridine m), 6.90(1H, d), 6.57(1H, d), 3.71-3.60(4H, m)mitropyridine-2-amino-ethyl)- amide  70 1 7-hydroxy-2-phenyl-1H-benzo-2-(2-aminoethyl)- 2 8.71(1H, d), 8.44(1H, t), 8.13-7.99(4H, m), 358imidazole-4-carboxylic acid(2- pyridine 7.85(1H, t), 7.76-7.70(2H, m),6.99(1H, d), pyridine-2-yl-ethyl)-amide 6.83(1H, d), 3.97(2H, t),3.42(2H, t)  71 2 2-(4-chloro-phenyl)-7-hydroxy- phenethylamine 2 δ8.03(2H, d), 7.79(1H, d), 7.64(2H, m), 3911H-benzoimidazole-4-carboxylic 7.37-7.15(5H, m), 6.84(1H, d), 3.75(2H,t), acid phenethyl amide 2.99(2H, t)  72 22-(4-chloro-phenyl)-7-hydroxy- 4-nitrophenethylamine 2 δ 8.18(2H, d),8.05(2H, d), 7.80(1H, d), 7.64(2H, 436 1H-benzoimidazole-4-carboxylicd), 7.56(2H, d), 6.88(1H, d), 3.80(2H, t), acid(4-nitro-phenethyl)-amide3.11(2H, t)  73 2 2-(4-chloro-phenyl)-7-hydroxy- 4-aminophenethylamine 2δ 8.11(2H, d), 7.83(1H, d), 7.64(2H, d), 7.50(2H, 4061H-benzoimidazole-4-carboxylic d), 7.31(2H, d), 6.82(1H, d), 3.78(2H,t), acid(4-amino-phenethyl)-amide 3.07(2H, t)  74 22-(4-chloro-phenyl)-7-hydroxy- 4-hydroxyphenethylamine 2 δ 7.82(1H, d),7.73(2H, d), 7.65(2H, d), 407 1H-benzoimidazole-4-carboxylic 7.12(2H,d), 7.00(1H, d), 6.86(1H, d), 6.74(1H, acid(4-hydroxy-phenethyl)- d),3.71(2H, t), 2.87(2H, t) amide  75 2 2-(4-chloro-phenyl)-7-hydroxy-N-[4-(2-amino-ethyl- 2 δ 8.08(2H, d), 7.79(1H, d), 7.69(2H, d), 4841H-benzoimidazole-4-carboxylic phenyl)-methane- 7.29-7.16(4H, dd),6.89(1H, d), 3.71(2H, t), acid[2-(4-methanesulfonyl- sulfonamide2.95(2H, t), 2.88(3H, s) amino-phenyl)-ethyl]-amide  76 22-(4-chloro-phenyl)-7-hydroxy- N-[4-(2-amino-ethyl)- 2 δ 8.08(2H, d),7.77(1H, d), 7.69(2H, d), 7.55(1H, 560 1H-benzoimidazole-4-carboxylicphenyl]-4-methyl- d), 7.15(3H, m), 6.98(2H, d), 6.88(1H, d),acid{2-[4-(toluene-4- benzenesulfonamide 3.65(2H, t), 2.86(2H, t),2.31(3H, s) sulfonylamino)-phenyl]-ethyl}- amine  77 22-(4-chloro-phenyl)-7-hydroxy- 3-hydroxy-4-methoxy- 2 δ 8.10-7.37(3H,m), 7.36-6.43(6H, m), 437 1H-benzoimidazole-4-carboxylic phenethylamine3.72(3H, s), 3.70(2H, t), 2.81(2H, t) acid(3-hydroxy-4-methoxy-phenethyl)-amide  78 2 2-(4-chloro-phenyl)-7-hydroxy- 4-(2-aminoethyl) 2δ 8.16(2H, d), 7.88(1H, d), 7.70(2H, d), 6.94(1H, 4001H-benzoimidazole-4-carboxylic morpholine d), 4.14-3.92(2H, m), 3.90(2H,t), 3.89-3.72(2H, acid(2-morpholin-4-yl-ethyl)- m), 3.84-3.57(2H, m),3.48(2H, t), amide 3.30-3.04(2H, m)  79 2 2-(4-chloro-phenyl)-7-hydroxy-2-[4-(2-amino-ethyl)- 2 δ 8.10(2H, d), 7.91-7.85(4H, m), 7.80(1H, d),536 1H-benzoimidazole-4-carboxylic phenyl]-isoindole-1,3- 7.68(2H, m),6.98(1H, d), 7.40(4H, dd), 6.93(1H, acid-2-[4-(1,3-dioxo-1,3- dione m),3.75(2H, t), 3.07(2H, t) dihydro-isoindole-2-yl)-phenyl]- ethyl-amide 80 2 2-(4-chloro-phenyl)-7-hydroxy- N-[4-(2-amino-ethyl- 2 δ8.13-8.05(3H, m), 7.80-7.65(3H, m), 498 1H-benzoimidazole-4-carboxylicphenyl]-ethane- 7.28-7.16(4H, m), 3.69(2H, t), 2.99(2H, q),acid[2-(4-ethanesulfonyl- sulfonamide 2.89(2H, t), 1.28(3H, t)amino-phenyl)-ethyl]-amide  81 2 2-(4-chloro-phenyl)-7-hydroxy-2-(2-aminoethylamino)-5- 2 δ 8.83(1H, d), 8.11-8.05(1H, m),7.86-7.81(3H, 452 1H-benzoimidazole-4-carboxylic nitropyridine m),7.68-7.60(2H, m), 6.90(1H, d), acid(5-nitropyridine-2-amino-6.60-6.54(1H, d), 3.71-3.60(4H, m) ethyl)-amide  82 22-(4-chloro-phenyl)-7-hydroxy- 2-(2-aminoethyl)- 2 δ 8.70(1H, d),8.43(1H, t), 8.13-8.09(3H, m), 392 1H-benzoimidazole-4-carboxylicpyridine 8.01(1H, d), 7.94(1H, d), 7.77(1H, d), 7.61(2H,acid(2-pyridine-2-yl-ethyl)- d), 4.01(2H, t), 3.42(2H, t) amide  83 22-(4-chloro-phenyl)-7-hydroxy- histamine 2 δ 8.81(s, 1H), 8.12(d, 2H),7.80(d, 1H), 7.65(d, 1H-benzoimidazole-4-carboxylic 2H), 7.40(s, 1H),6.83(d, 1H), 3.84(t, 2H), acid[2-(1H-imidazol-4-yl)- 3.12(t, 2H)ethyl]amine  84 2 2-(4-chloro-phenyl)-7-hydroxy- 4-hydroxyphenethylamine2 δ 8.05(d, 2H), 7.79(d, 1H), 7.65(d, 2H), 7.12(d,1H-benzoimidazole-4-carboxylic 2H), 6.85(d, 1H), 6.72(d, 2H), 3.70(t,2H), acid[2-(4-hydroxy-phenyl)- 2.87(t, 2H) ethyl]-amide  85 22-(4-Chloro-phenyl)-7-hydroxy- 4-acetyl-2-pyridiylethyl 2 δ 8.57(s, 1H),8.20˜8.00(m, 3H), 8.02(br, 1H), 1H-benzoimidazole-4-carboxylic amine7.75˜7.60(m, 3H), 7.38(d, 1H), 6.88(d, 1H), acid[2-(5-acetylamino-4.12(t, 2H), 3.68(t, 2H), 2.12(s, 3H) pyridin-2-ylamino)-ethyl]-amide 86 2 2-(4-chloro-phenyl)-7-hydroxy- N-[4-(2-amino-ethyl)- 2 δ 8.03(m,2H), 7.80(d, 1H), 7.60(d, 2H), 7.57(d, 1H-benzoimidazole-4-carboxylicphenyl]-2-(4-methyl- 2H), 7.29(d, 2H), 6.83(d, 1H), 3.75(t, 2H),acid(2-{4-[2-(4-methyl- piperazin-1-yl)- 3.34(s, 2H), 3.10˜2.75(m, 13H)piperazin-1-yl)-acetyl-amino]- acetamide phenyl}-ethyl)-amide  87 22-(4-chloro-phenyl)-7-hydroxy- N-[4-(2-amino-ethyl)- 2 δ 8.03(m, 2H),7.79(d, 1H), 7.61(d, 2H), 7.53(d, 1H-benzoimidazole-4-carboxylicphenyl]-2-(4-ethyl- 2H), 7.29(d, 2H), 6.84(d, 1H), 3.75(t, 2H),acid(2-{4-[2-(4-ethyl- piperazin-1-yl)-acetamide 3.34(s, 2H), 3.25(q,2H), 3.05˜2.75(m, 8H), piperazin-1-yl)-acetylamino]- 1.35(t, 3Hphenyl}-ethyl)-amide  88 2 2-(4-chloro-phenyl)-7-hydroxy-N-[4-(2-amino-ethyl)- 2 δ 8.03(d, 2H), 7.80(d, 1H), 7.60(d, 2H), 7.54(t,1H-benzoimidazole-4-carboxylic phenyl]-2-dimethyl- 2H), 7.32(d, 2H),6.81(d, 1H), 4.08(s, 2H), acid{2-[4-(2-dimethylamino- amino-acetamide3.76(t, 2H), 2.95(m, 8H) acetylamino)-phenyl]-ethyl}- amide  89 22-(4-chloro-phenyl)-7-hydroxy- N-[4-(2-amino-ethyl)- 2 δ 8.02(d, 2H),7.80(d, 1H), 7.60(d, 2H), 7.54(d, 1H-benzoimidazole-4-carboxylicphenyl]-2-diethylamino- 2H), 7.32(d, 2H), 6.81(d, 1H), 4.06(s, 2H),acid{2-[4-(2-diethylamino- acetamide 3.77(t, 2H), 3.32(q, 4H), 2.99(t,2H), 1.35(t, 6H) acetylamino)-phenyl]-ethyl}- amide  90 22-(4-chloro-phenyl)-7-hydroxy- 4-aminophenethylamine 2 δ 8.13(d, 2H),7.78(d, 1H), 7.62(d, 2H), 7.51(d, 1H-benzoimidazole-4-carboxylic 2H),7.29(d, 2H), 6.77(d, 1H), 3.79(t, 2H), acid[2-(4-amino-phenyl)- 3.69(t,2H ethyl]-amide  91 2 2-(4-chloro-phenyl)-7-hydroxy- N-(2-amino-ethyl)-2 δ 8.73(s, 1H), 8.22(d, 1H), 8.09(d, 1H), 7.88(m,1H-benzoimidazole-4-carboxylic pyridine-2,5-diamine 2H), 7.60(d, 1H),7.47(d, 1H), 7.13(d, 1H), acid[2-(5-amino-pyridin-2- 6.78(m, 1H),3.87(t, 2H), 3.75(t, 2H) ylamino)-ethyl]-amide  92 22-(4-chloro-phenyl)-7-hydroxy- N-[4-(2-amino-ethyl)- 2 δ 8.03(d, 2H),7.80(d, 1H), 7.60(d, 2H), 7.54(d, 1H-benzoimidazole-4-carboxylicphenyl]-2-morpholin-4- 2H), 7.31(d, 2H), 6.81(d, 1H), 3.12(s, 2H),acid{2-[4-(2-morpholin-4-yl- yl-acetamide 3.98(br, 4H), 3.77(t, 2H),3.44(br, 4H), 2,98(t, acetylamino)-phenyl]-ethyl}- 2H) amide  93 22-(4-chloro-phenyl)-7-hydroxy- N,N-(dimethylamino)- 2 δ 8.13(d, 2H),7.78(d, 1H), 7.62(d, 2H), 7.51(d, 1H-benzoimidazole-4-carboxylicphenethylamine 2H), 7.29(d, 1H), 6.77(d, 1H), 3.81(t, 2H),acid[2-(4-dimethylamino- 3.15(s, 6H), 3.08(t, 2H) phenyl)-ethyl]-amide 94 2 2-(4-chloro-phenyl)-7-hydroxy- 2-[4-(2-morpholin-4-yl- 2 δ 8.06(d,2H), 7.79(d, 1H), 7.73(d, 2H), 7.28(d, 1H-benzoimidazole-4-carboxylicethoxy)-phenyl]- 2H), 6.94(d, 2H), 6.83(d, 1H), 4.31(m, 2H),acid{2-[4-(2-morpholin-4-yl- ethylamine 3.99(br, 2H), 3.95˜3.65(m, 4H),3.65˜3.50(m, ethoxy)phenyl]-ethyl}-amide 4H), 3.32(m, 2H), 2.95(m, 2H) 95 2 2-(4-chloro-phenyl)-7-hydroxy- 2-{4-[2-(4-methyl- 2 δ 8.17(d, 2H),7.78(d, 1H), 7.40(t, 2H), 7.23(d, 1H-benzoimidazole-4-carboxylicpiperazin-1-yl)-ethoxy]- 2H), 6.90(m, 3H), 4.25(t, 2H), 3.67(t, 2H),acid(2-{4-]2-(4-methyl- phenyl}-ethylamine 3.50˜3.30(m, 10H), 2.90(m,5H) piperazin-1-yl)ethoxy]-phenyl}- ethyl)-amide  96 22-(4-chloro-phenyl)-7-hydroxy- 2-hydroxyphenethyl- 2 δ 8.05(d, 2H),7.79(d, 1H), 7.62(d, 2H), 7.18(d, 1H-benzoimidazole-4-carboxylic amine1H), 07.05(d, 1H), 6.90˜6.70(m, 3H), 3.70(t, acid[2-(2-hydroxy-phenyl)-2H), 3.02(t, 2H) ethyl]-amide  97 2 2-(4-chloro-phenyl)-7-hydroxy-2-methoxyphenethylamine 2 δ 8.00(d, 2H), 7.81(d, 1H), 7.57(d, 2H),7.24(d, 1H-benzoimidazole-4-carboxylic 1H), 6.95(m, 1H), 6.85(m, 1H),6.73(d, 2H), acid[2-(2-methoxy-phenyl)- 3.76(s, 3H), 3.64(t, 2H),2.98(t, 2H) ethyl]-amide  98 2 2-(4-chloro-phenyl)-7-hydroxy-3-bromophenethylamine 2 δ 8.00(d, 2H), 7.79(d, 1H), 7.02˜7.50(m, 3H),1H-benzoimidazole-4-carboxylic 7.40˜7.20(m, 3H), 6.74(d, 1H), 3.81(t,2H), acid[2-(3-bromo-phenyl)- 3.01(t, 2H) ethyl]-amide  99 32-(2,4-dichloro-phenyl)-7- phenethylamine 2 δ 7.92-7.66(3H, m),7.65-7.38(1H, m), 425 hydroxy-1H-benzoimidazole-4- 7.37-7.00(5H, m),7.44-7.18(5H, m), 6.85(1H, carboxylic acid phenethyl-amide d), 3.68(2H,t), 2.98(2H, t) 100 3 2-(2,4-dichloro-phenyl)-7- 4-nitrophenethylamine 2δ 8.08(2H, d), 7.90-7.31(5H, m), 7.20-6.97(1H, 470hydroxy-1H-benzoimidazole-4- m), 6.82(1H, d), 3.76(2H, t), 3.09(2H, t)carboxylic acid(4-amino- phenethyl)-amide 101 32-(2,4-dichloro-phenyl)-7- 4-hydroxy-3-methoxy- 2 δ 7.95-7.68(3H, m),7.67-7.40(2H, m), 471 hydroxy-1H-benzoimidazole-4- phenethylamine7.20-6.92(1H, m), 6.82(2H, t), 6.68(1H, d), carboxylic acid(4-hydroxy-3-3.72(2H, t), 3.60(3H, s), 2.88(2H, t) methoxy-phenethyl)-amide 102 32-(2,4-dichloro-phenyl)-7- 3-hydroxy-4-methoxy- 2 δ 8.10-7.37(3H, m),7.36-6.43(6H, m), 3.72(3H, 471 hydroxy-1H-benzoimidazole-4-phenethylamine s), 3.70(2H, t), 2.81(2H, t) carboxylic acid(3-hydroxy-4-methoxy-phenethyl)-amide 103 3 2-(2,4-dichloro-phenyl)-7-ethylenediamine 2 δ 8.10(2H, d), 7.88(1H, d), 7.66(2H, d), 364hydroxy-1H-benzoimidazole-4- 7.37-7.23(4H, m), 6.92(1H, d), 3.77(2H, t),carboxylic acid(2-amino-ethyl)- 3.25(2H, t) amide 104 32-(2,4-dichloro-phenyl)-7- 4-hydroxyphen- 2 δ 7.94-7.64(3H, m),7.62-7.39(1H, m), 441 hydroxy-1H-benzoimidazole-4- ethylamine7.28-6.97(3H, m), 6.96-6.78(1H, m), 6.68(1H, carboxylic acid(4-hydroxy-d), 3.64(2H, t), 2.82(2H, t) phenethyl)-amide 105 32-(2,4-dichloro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 7.95-7.70(2H, m),7.69-7.43(3H, m), 594 hydroxy-1H-benzoimidazole-4- phemphenyl]-4-methyl-7.42-7.23(3H, m), 7.22-7.03(2H, m), 7.01(1H, carboxylic acid{2-[4-benzenesulfonamide d), 6.98-6.77(2H, m), 3.81-3.52(2H, m),(toluene-4-sulfonylamino)- 3.10-2.73(2H, m), 3.01(1H, t), 2.88(1H, t),phenyl]-ethyl}-amide 2.48(3H, s) 106 3 2-(2,4-dichloro-phenyl)-7-N-[4-(2-amino-ethyl)- 2 δ 7.92-7.78(3H, m), 7.68(1H, d), 7.24(4H, dd),518 hydroxy-1H-benzoimidazole-4- phenyl]-methane 6.96(1H, d), 3.68(2H,t), 2.93(2H, t), 2,90(3H, s) carboxylic acid[2-(4-methane- sulfonamidesulfonylamino-phenyl)-ethyl]- amide 107 3 2-(2,4-dichloro-phenyl)-7-2-[4-(2-amino-ethyl)- 2 δ 7.92-7.83(7H, m), 7.67(1H, d), 7.38(4H, dd),570 hydroxy-1H-benzoimidazole-4- phenyl]-isoindole-1,3- 6.98(1H, d),3.72(2H, t), 3.05(2H, t) carboxylic acid{2-[4-(1,3- dionedioxo-1,3-dihydro-isoindole-2- yl)-phenyl]-ethyl}-amide 108 32-(2,4-dichloro-phenyl)-7- 4-(2-aminoethyl)- 2 δ 8.02-7.80(3H, m),7.65(1H, d), 6.98(1H, d), 434 hydroxy-1H-benzoimidazole-4- morpholine4.14-3.92(2H, m), 3.88(2H, t), 3.89-3.72(2H, carboxylicacid(2-morpholin-4- m), 3.84-3.57(2H, m), 3.44(2H, t), yl-ethyl)-amide3.30-3.04(2H, m) 109 3 2-(2,4-dichloro-phenyl)-7- N-[4-(2-amino-ethyl)-2 δ 7.91-7.75(3H, m), 7.68(1H, d), 7.21(4H, dd), 532hydroxy-1H-benzoimidazole-4- phenyl]-ethanesulfonamide 6.99(1H, d),3.66(2H, t), 2.99(2H, q), 2.89(2H, t), carboxylic acid[2-(4- 1.28(3H, t)ethanesulfonylamino-phenyl)- ethyl]-amide 110 32-(2,4-dichloro-phenyl)-7- 2-(2-aminoethylamino)- 2 δ 8.83(1H, d),8.11-8.05(1H, m), 7.86-7.81(3H, 486 hydroxy-1H-benzoimidazole-4-5-nitropyridine m), 7.68-7.60(1H, m), 6.90(1H, d), carboxylicacid(5-nitropyridine- 6.60-6.54(1H, d), 3.71-3.60(4H, m)2-amino-ethyl)-amide 111 3 2-(2,4-dichloro-phenyl)-7-2-(2-aminoethyl)-pyridine 2 δ 8.70(1H, d), 8.40(1H, t), 8.07-7.50(6H,m), 426 hydroxy-1H-benzoimidazole-4- 6.83(1H, d), 3.95(2H, t), 3.38(2H,t) carboxylic acid(2-pyridin-2-yl- ethyl)-amide 112 32-(2,4-dichloro-phenyl)-7- 4-(acetylamino)phen- 2 δ 7.85˜7.78(m, 3H),7.61(d, 1H), 7.25(d, 2H), hydroxy-1H-benzoimidazole-4- ethylamine7.15(d, 2H), 6.86(d, 1H), 3.69(t, 2H), 2.95(t, carboxylicacid[2-(4-acetyl- 2H), 2.88(s, 3H) amino-phenyl)-ethyl]-amide 113 32-(2,4-dichloro-phenyl)-7- 4-(pentanoylamino)- 2 δ 7.90˜7.80(m, 3H),7.72(d, 1H), 7.61(d, 2H), hydroxy-1H-benzoimidazole-4- phenethylamine7.20(d, 2H), 6.89(d, 1H), 3.68(t, 2H), 2.89(t, 2H), carboxylicacid[2-(4-pentanoyl- 2.35(t, 2H), 1.65(m, 2H), 1.38(m, 2H), 0.96(t,amino-phenyl)ethyl]-amide 3H) 114 4 2-(4-fluoro-phenyl)-7-N-[4-(2-amino-ethyl)- 2 δ 8.15-8.10(2H, m), 7.78(1H, d), 7.46(2H, t),hydroxy-1H-benzoimidazole-4- phenyl]-methane- 7.27(2H, d), 7.18(2H, d),6.87(1H, d), 3.70(2H, carboxylic acid[2-(4-methane- sulfonamide t),2.97(2H, t), 2.87(3H, s) sulfonylamino-phenyl)-ethyl]- amide 115 42-(4-fluoro-phenyl)-7- N-[4-(2-amino-ethyl)- 2hydroxy-1H-benzoimidazole-4- phenyl]-p-toluene- carboxylicacid{2-[4-(toluene- sulfonamide 4-sulfonylamino)phenyl]- ethyl}-amide116 4 2-(4-fluoro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 8.17(2H, m),7.77(1H, d), 7.44(2H, t), 7.25(2H, hydroxy-1H-benzoimidazole-4-phenyl]-ethane- d), 7.17(2H, d), 6.92(1H, d), 3.67(2H, t), carboxylicacid[2-(4-ethane- sulfonamide 3.02(2H, q), 2.96(2H, t), 1.26(3H, t)sulfonylamino-phenyl)-ethyl]- amide 117 4 2-(4-fluoro-phenyl)-7-N-[4-(2-amino-ethyl)- 2 δ 8.1˜8.2(m, 2H), 7.58(d, 1H), 7.44(m, 4H),hydroxy-1H-benzoimidazole-4- phenyl]-acetamide 7.34(m, 2H), 6.92(d, 1H),3.66(t, 2H), 2.90(t, carboxylic acid[2-(4-acetyl- 2H), 2.09(s, 1H)amino-phenyl)-ethyl]-amide 118 4 2-(4-fluoro-phenyl)-7-2-(4-methyl-piperazin-1- 2 δ 8.25˜8.16(m, 2H), 8.05(d, 1H), 7.48˜7.37(m,hydroxy-1H-benzoimidazole-4- yl)-ethylamine 2H), 6.88(d, 1H),3.70˜3.50(m, 10H), 3.14(t, carboxylic acid[2-(4-methyl- 2H), 2.96(s,3H), 2.12(t, 2H) piperazin-1-yl)-ethyl]-amide 119 42-(4-fluoro-phenyl)-7- 2-morpholin-4-yl- 2 δ 8.22(m, 2H), 7.85(d, 1H),7.41(t, 2H), 6.90(d, hydroxy-1H-benzoimidazole-4- ethylamine 1H),4.20˜3.60(m, 8H), 3.48(t, 2H), carboxylic acid(2-morpholin-4-3.34˜3.10(br, 2H) yl-ethyl)-amide 120 4 2-(4-fluoro-phenyl)-7- pentanoicacid 2 δ 8.08(m, 2H), 7.74(d, 1H), 7.45( d, 2H), 7.35(t,hydroxy-1H-benzoimidazole-4- [4-(2-amino-ethyl)- 2H), 7.18(d, 2H),6.86(d, 1H), 3.66(t, 2H), 2.86(t, carboxylic acid[2-(4-pentanoyl-phenyl]-amide 2H), 2.33(t, 2H), 1.64(m, 2H), 1.39(m, 2H),amino-phenyl)-ethyl]-amide 0.93(t, 3H) 121 4 2-(4-fluoro-phenyl)-7-4-hydroxyphenethylamine 2 δ 8.14(m, 2H), 7.78(d, 1H), 7.44(t, 2H),7.09(d, hydroxy-1H-benzoimidazole-4- 2H), 6.89(d, 1H), 6.72(d, 2H),3.66(t, 2H), carboxylic acid[2-(4-hydroxy- 2.86(t, 2H)phenyl)-ethyl]-amide 122 4 2-(4-fluoro-phenyl)-7- N-(4-nitro-pyridin-2-2 δ 8.84(s, 1H), 8.21˜8.17(m, 3H), 7.79(d, 1H),hydroxy-1H-benzoimidazole-4- yl)-ethane-1,2-diamine 7.44(t, 2H), 6.92(d,1H), 6.63(br, 1H), carboxylic acid[2-(5-nitro- 3.90˜3.60(m, 4H)pyridin-2-ylamino)-ethyl]-amide 123 4 2-(4-fluoro-phenyl)-7-N-[6-(2-Amino-ethyl- 2 δ 8.24˜8.19(m, 2H), 7.95˜7.75(m, 3H), 7.43(t,hydroxy-1H-benzoimidazole-4- amino)-pyridin-3-yl]- 2H), 7.15(d, 1H),6.92(d, 1H), 3.80˜3.65(m, 4H), carboxylic acid[2-(5-methane-methanesulfonamide 2.99(t, 3H) sulfonylamino-pyridin-2-ylamino)-ethyl]-amide 124 4 2-(4-fluoro-phenyl)-7-N-[6-(2-amino-ethylamino)- 2 δ 8.23(m, 2H), 7.81(d, 1H), 7.52(m, 4H),hydroxy-1H-benzoimidazole-4- pyridin-3-yl]-p- 7.40˜7.20(m, 4H), 7.01(d,1H), 6.82(d, 1H), carboxylic acid{2-[5-(toluene- toluenesulfonamide3.75(t, 2H), 3.66(t, 2H), 2.36(s, 3H) 4-sulfonylamino)-pyridin-2-ylamino]-ethyl}-amide 125 4 2-(4-fluoro-phenyl)-7- histamine 2 δ08.81(s, 1H), 8.19(m, 2H), 7.80(d, 1H), hydroxy-1H-benzoimidazole-4-7.50˜7.30(m, 3H), 6.90(d, 1H), 3.80(t, 2H), carboxylicacid[2-(1H-imidazol- 3.11(t, 2H) 4-yl)-ethyl]-amide 126 42-(4-fluoro-phenyl)-7- N-[6-(2-amino-ethylamino)- 2 δ 8.58(s, 1H),8.22(m, 2H), 8.04(br, 1H), 7.69(d, hydroxy-1H-benzoimidazole-4-pyridin-3-yl]-acetamide 1H), 7.50˜7.35(m, 3H), 6.90(d, 1H), 4.11(t, 2H),carboxylic acid[2-(5-acetyl- 3.69(t, 2H), 2.11(s, 3H)amino-pyridin-2-yl-amino)- ethyl]-amide 127 4 2-(4-fluoro-phenyl)-7-N-[4-(2-amino-ethyl)- 2 δ 8.10˜7.80(m, 2H), 7.69(d, 1H), 7.43(d, 2H),hydroxy-1H-benzoimidazole-4- phenyl]-2-(4-methyl- 7.25(t, 2H), 7.19(d,2H), 6.76(d, 1H), 3.63(t, 2H), carboxylic acid(2-{4-[2-(4-piperazin-1-yl)-acetamide 3.21(s, 2H), 2.90˜2.78(m, 13H)methyl-piperazin-1-yl)-acetyl- amino]-phenyl}-ethyl)-amide 128 42-(4-fluoro-phenyl)-7- N-[4-(2-amino-ethyl)- 2 δ 8.13(m, 2H), 7.79(d,1H), 7.52(d, 2H), 7.37(t, hydroxy-1H-benzoimidazole-4-phenyl]-2-(4-ethyl- 2H), 7.27(d, 2H), 6.85(d, 1H), 3.72(t, 2H),carboxylic acid(2-{4-[2-(4- piperazin-1-yl)-acetamide 3.30(s, 2H),3.24(q, 2H), 3.05˜2.85(m, 10H), ethyl-piperazin-1-yl)-acetyl- 1.35(t,3H) amino]-phenyl}-ethyl)-amide 129 4 2-(4-fluoro-phenyl)-7-N-[4-(2-amino-ethyl)- 2 δ 8.11(m, 2H), 7.78(d, 1H), 7.53(d, 2H),hydroxy-1H-benzoimidazole-4- phenyl]-2-dimethyl- 7.40˜7.25(m, 4H),6.83(d, 1H), 4.09(s, 2H), carboxylic acid{2-[4-(2- amino-acetamide3.74(t, 2H), 2.94(m, 8H) dimethylamino-acetylamino)-phenyl]-ethyl}-amide 130 4 2-(4-fluoro-phenyl)-7- N-[4-(2-amino-ethyl)-2 δ 8.13(m, 2H), 7.79(d, 1H), 7.54(d, 2H), 7.39(t,hydroxy-1H-benzoimidazole-4- phenyl]-2-diethyl- 2H), 7.30(d, 2H),6.86(d, 1H), 4.08(s, 2H), carboxylic acid{2-[4-(2- amino-acetamide3.72(t, 2H), 3.33(q, 4H), 2.96(t, 2H), 1.35(t, 6H)diethylamino-acetylamino)- phenyl]-ethyl}-amide 131 42-(4-fluoro-phenyl)-7- 4-aminophenethylamine 2 δ 8.20(m, 2H), 7.79(d,1H), 7.49(d, 2H), 7.42(t, hydroxy-1H-benzoimidazole-4- 2H), 7.32(d, 2H),6.86(d, 1H), 3.74(t, 2H), carboxylic acid[2-(4-amino- 3.06(t, 2H)phenyl)-ethyl]-amide 132 4 2-(4-fluoro-phenyl)-7- 2-(4-morpholin-4-yl- 2δ 8.14(m, 2H), 7.78(d, 1H), 7.41(d, 2H), 7.35(d,hydroxy-1H-benzoimidazole-4- phenyl)-ethylamine 1H), 7.14(d, 2H),6.85(d, 1H), 3.89(m, 4H), carboxylic acid[2-(4- 3.71(t, 2H), 3.28(m,4H), 2.96(t, 2H) morpholin-4-yl-phenyl)- ethyl]-amide 133 42-(4-fluoro-phenyl)-7- {1-[4-(2-amino-ethyl)- 2 δ 8.13(m, 1H), 7.78(d,1H), 7.32˜7.20(m, 4H), hydroxy-1H-benzoimidazole-4-phenyl]-pyrrolidin-3-yl}- 7.11(s, 1H), 6.74(m, 2H), 6.48(d, 1H), 3.60(t,carboxylic acid{2-[4-(3- diethyl-amine 2H), 2.90(t, 2H), 2.82˜2.71(m,6H), 2.40(q, diethylamino-pyrrolidin-1-yl)- 4H), 1.65(m, 1H), 1.02(t,6H) phenyl]-ethyl}-amide 134 4 2-(4-fluoro-phenyl)-7-N-[4-(2-amino-ethyl)- 2 δ 8.15(m, 2H), 7.79(d, 1H), 7.53(d, 2H), 7.39(t,hydroxy-1H-benzoimidazole-4- phenyl]-2-morpholin-4- 2H), 7.29(d, 2H),6.87(d, 1H), 4.13(s, 2H), carboxylic acid{2-[4-(2- yl-acetamide 3.97(br,4H), 3.72(q, 2H), 3.44(br, 4H), 2.97(t, morpholin-4-yl-acetylamino)- 2H)phenyl]-ethyl}-amide 135 4 2-(4-fluoro-phenyl)-7- N,N-(dimethylamino)- 2δ 8.20(m, 3H), 7.78(d, 1H), 7.54(m, 3H), 7.43(t,hydroxy-1H-benzoimidazole-4- phenethylamine 2H), 6.84(d, 1H), 3.75(t,2H), 3.21(s, 6H), carboxylic acid[2-(4-dimethyl- 3.07(t, 2H)amino-phenyl)-ethyl]-amide 136 4 2-(4-fluoro-phenyl)-7-2-[4-(2-morpholin-4-yl- 2 δ 8.18(m, 2H), 7.79(d, 1H), 7.42(t, 2H),7.26(d, hydroxy-1H-benzoimidazole-4- ethoxy)phenyl]- 2H), 7.00˜6.85(m,3H), 4.33(m, 2H), carboxylic acid{2-[4-(2- ethylamine 4.10˜4.00(br, 2H),3.95˜3.75(br, 2H), morpholin-4-yl-ethoxy)-phenyl]- 3.75˜3.50(m, 8H),3.32(m, 4H), 2.95(m, 2H) ethyl}-amide 137 4 2-(4-fluoro-phenyl)-7-2-hydroxyphenethylamine 2 δ 8.18(m, 2H), 7.78(d, 1H), 7.38(t, 2H),7.14(d, hydroxy-1H-benzoimidazole-4- 1H), 7.03(d, 1H), 6.88˜6.74(m, 3H),3.77(t, 2H), carboxylic acid[2-(2-hydroxy- 2.98(t, 2H)phenyl)-ethyl]-amide 138 4 2-(4-fluoro-phenyl)-7- 2-methoxyphen- 2 δ8.18˜8.05(m, 2H), 7.78(d, 1H), 7.45˜7.25(m, hydroxy-1H-benzoimidazole-4-ethylamine 3H), 7.20(m, 2H), 6.95(d, 1H), 6.82(d, 1H), carboxylicacid[2-(2-methoxy- 3.78(s, 3H), 3.73(t, 2H), 2.99(t, 2H)phenyl)-ethyl]-amide 139 4 2-(4-fluoro-phenyl)-7- 3-bromophenethylamine2 δ 8.12(m, 2H), 7.80(d, 1H), 7.49(s, 1H), hydroxy-1H-benzoimidazole-4-7.38˜7.18(m, 5H), 6.83(d, 1H), 3.76(t, 2H), carboxylic acid[2-(3-bromo-2.97(t, 2H) phenyl)-ethyl]-amide 140 5 2-(2,4-difluoro-phenyl)-7-N-[4-(2-amino-ethyl)- 2 δ 7.92-7.89(1H, m), 7.74(1H, m), 7.30-7.11(6H,hydroxy-1H-benzoimidazole-4- phenyl]-methane- m), 6.74(1H, d), 3.67(2H,bs), 2.89(2H, bs), carboxylic acid[2-(4-methane- sulfonamide 2.82(3H, s)sulfonylamino-phenyl)-ethyl]- amide 141 5 2-(2,4-difluoro-phenyl)-7-N-[4-(2-amino-ethyl)- 2 δ 7.99(1H, m), 7.74(1H, d), 7.50(2H, d),hydroxy-1H-benzoimidazole-4- phenyl]-p-toluene- 7.33-7.26(2H, m),7.23(4H, m), 6.94(2H, d), carboxylic acid{2-[4-(toluene- sulfonamide6.81(1H, d), 3.58(2H, t), 2.82(2H, t), 2.23(3H, s)4-sulfonylamino)-phenyl]- ethyl}amide 142 5 2-(2,4-difluoro-phenyl)-7-N-[4-(2-amino-ethyl)- 2 δ 8.06(1H, d), 7.81(1H, d), 7.51-7.15(6H, m),hydroxy-1H-benzoimidazole-4- phenyl]-ethanesulfonamide 6.88(1H, d),3.67(2H, t), 3.01(2H, q), 2.92(2H, carboxylic acid[2-(4-ethane- t),1.25(3H, m) sulfonylamino-phenyl)-ethyl]- amide 143 62-(2-chloro-4-fluoro-phenyl)- N-[4-(2-amino-ethyl)- 2 δ 7.94(1H, m),7.84(1H, m), 7.62(1H, m), 7-hydroxy-1H-benzoimidazole- phenyl]-methane-7.43(2H, m), 7.38-7.24(3H, m), 6.95(1H, d), 4-carboxylicacid[2-(4-methane- sulfonamide 3.65(2H, t), 2.99-2.83(5H, m)sulfonylamino-phenyl)-ethyl]- amide 144 6 2-(2-chloro-4-fluoro-phenyl)-N-[4-(2-amino-ethyl)- 2 δ 7.91(1H, m), 7.81(1H, d), 7.62-7.54(3H,7-hydroxy-1H-benzoimidazole- phenyl]-p-toluene- m), 7.42(1H, m),7.20-7.11(4H, m), 4-carboxylic acid{2-[4- sulfonamide 7.05-6.93(3H, m),3.61(2H, t), 2.86(2H, t), toluene-4-sulfonylamino)- 2.32(3H, s)phenyl]-ethyl}amide 145 6 2-(2-chloro-4-fluoro-phenyl)-N-[4-(2-amino-ethyl)- 2 δ 7.83(2H, m), 7.56(1H, m), 7.36(1H, m),7-hydroxy-1H-benzoimidazole- phenyl]-ethane- 7.18-7.11(4H, m),7.38-7.24(3H, m), 6.92(1H, 4-carboxylic acid[2-(4- sulfonamide d),3.60(2H, t), 2.99(4H, m), 1.23(3H, s) ethanesulfonylamino-phenyl)-ethyl]-amide 146 6 2-(2-chloro-4-fluoro-phenyl)- N-[4-(2-amino-ethyl)- 2δ 8.00˜7.91(m, 2H), 7.57(d, 1H), 7.48˜7.34(m,7-hydroxy-1H-benzoimidazole- phenyl]-acetamide 3H), 7.19(d, 2H), 6.92(d,1H), 3.66(t, 2H), 4-carboxylic acid[2-(4- 2.9(t, 2H), 2.09(s, 3H)acetylamino-phenyl)-ethyl]- amide 147 6 2-(2-chloro-4-fluoro-phenyl)-2-morpholin-4-yl- 2 δ 8.00˜7.90(m, 2H), 7.60(d, 1H), 7.43(t, 1H),7-hydroxy-1H-benzoimidazole- ethylamine 6.95(d, 1H), 4.20˜3.60(m, 8H),3.46(t, 2H), 4-carboxylic acid(2-morpholin- 3.34˜3.10(br, 2H)4-yl-ethyl)-amide 148 6 2-(2-chloro-4-fluoro-phenyl)-2-(4-methyl-piperazin-1- 2 δ 7.98(m, 2H), 7.59(d, 1H), 7.40(t, 1H),6.93(d, 7-hydroxy-1H-benzoimidazole- yl)-ethylamine 1H), 3.80˜3.50(br,10H), 3.21(t, 2H), 2.95(s, 4-carboxylic acid[2-(4-methyl- 3H), 2.06(t,2H) piperazin-1-yl)-ethyl]-amide 149 6 2-(2-chloro-4-fluoro-phenyl)-pentanoic acid 2 δ 7.92˜7.82(m, 2H), 7.57(d, 1H), 7.46˜7.37(m,7-hydroxy-1H-benzoimidazole- [4-(2-amino-ethyl)- 3H), 7.20(d, 2H),6.92(d, 1H), 3.66(t, 2H), 2.91(t, 4-carboxylic acid[2-(4- phenyl]-amide2H), 2.34(t, 2H), 1.66(m, 2H), 1.40(m, 2H), pentanoylamino-phenyl)-0.95(t, 3H) ethyl]-amide 150 6 2-(2-chloro-4-fluoro-phenyl)-4-hydroxyphenethylamine 2 δ 7.92˜7.83(m, 2H), 7.62(d, 1H), 7.43(t, 1H),7-hydroxy-1H-benzoimidazole- 7.07(d, 2H), 6.94(d, 1H), 6.69(d, 2H),3.62(t, 4-carboxylic acid[2-(4-hydroxy- 2H), 2.85(t, 2H)phenyl)-ethyl]-amide 151 6 2-(2-chloro-4-fluoro-phenyl)-N-(5-nitro-pyridin-2- 2 δ 8.85(s, 1H), 8.12(br, 1H), 7.79˜7.85(m, 3H),7-hydroxy-1H-benzoimidazole- yl)-ethane-1,2-diamine 7.63(d, 1H), 7.42(t,1H), 6.95(d, 1H), 6.62(br, 4-carboxylic acid[2-(5-nitro- 1H),3.90˜3.60(m, 4H) pyridin-2-ylamino)-ethyl]-amide 152 62-(2-chloro-4-fluoro-phenyl)- N-[6-(2-amino-ethyl- 2 δ 8.05˜7.85(m, 3H),7.79(d, 1H), 7.61(d, 1H), 7-hydroxy-1H-benzoimidazole-amino)-pyridin-3-yl]- 7.42(t, 1H), 7.14(d, 1H), 6.94(d, 1H),4-carboxylic acid[2-(5- methanesulfonamide 3.80˜3.60(m, 4H), 2.92(t, 3H)methanesulfonylamino-pyridin- 2-ylamino)-ethyl]-amide 153 62-(2-chloro-4-fluoro-phenyl)- N-[6-(2-amino-ethyl- 2 δ 7.92(m, 1H),7.89(d, 1H), 7.58(d, 2H), 7.45(m, 7-hydroxy-1H-benzoimidazole-amino)-pyridin-3-yl]- 3H), 7.29(m, 3H), 6.92(d, 1H), 6.78(d, 1H),4-carboxylic acid{2-[5- p-toluenesulfonamide 3.72(t, 2H), 3.61(t, 2H),2.37(s, 3H) (toluene-4-sulfonylamino)- pyridin-2-ylamino]ethyl}- amide154 6 2-(2-chloro-4-fluoro-phenyl)- histamine 2 δ 8.79(s, 1H), 8.00˜7.02H), 7.62(d, 1H), 7-hydroxy-1H-benzoimidazole- 7.50˜7.35(m, 2H), 6.93(d,1H), 3.76(t, 2H), 4-carboxylic acid[2-(1H- 3.76(t, 2H), 3.10(t, 2H)imidazol-4-yl)-ethyl]-amide 155 6 2-(2-chloro-4-fluoro-phenyl)-N-[6-(2-amino-ethyl- 2 δ 8.57(s, 1H), 8.10˜7.95(m, 2H), 7.88(d, 1H),7-hydroxy-1H-benzoimidazole- amino)-pyridin-3-yl]- 7.74(d, 1H),7.50˜7.30(m, 2H), 6.95(d, 1H), 4-carboxylic acid[2-(5- acetamide 4.10(t,2H), 3.65(t, 2H), 2.13(s, 3H) acetylamino-pyridin-2-ylamino)-ethyl]-amide 156 6 2-(2-chloro-4-fluoro-phenyl)- N-[4-(2-Amino-ethyl)- 2δ 7.97˜7.80(m, 2H), 7.61(d, 1H), 7.59(d, 2H),7-hydroxy-1H-benzoimidazole- phenyl]-2-(4-methyl- 7.40(t, 1H), 7.25(d,2H), 6.92(d, 1H), 3.67(t, 2H), 4-carboxylic acid(2-{4-[2-piperazin-1-yl)-acetamide 3.34(s, 2H), 3.10˜2.75(m, 13H)(4-methyl-piperazin-1-yl)- acetylamino]-phenyl}-ethyl)- amide 157 62-(2-chloro-4-fluoro-phenyl)- N-[4-(2-amino-ethyl)- 2 δ 7.97˜7.83(m,2H), 7.61(d, 1H), 7.50(d, 2H), 7-hydroxy-1H-benzoimidazole-phenyl]-2-(4-ethyl- 7.39(t, 1H), 7.25(d, 2H), 6.91(d, 1H), 3.67(t, 2H),4-carboxylic acid(2-{4-[2- piperazin-1-yl)-acetamide 3.34(s, 4H),3.21(q, 2H), 3.05˜2.75(m, 8H), (4-ethyl-piperazin-1-yl)-acetyl- 1.35(t,3H) amino]-phenyl}-ethyl)amide 158 6 2-(2-chloro-4-fluoro-phenyl)-N-[4-(2-amino-ethyl)- 2 δ 7.99(m, 1H), 7.84˜7.70(m, 2H), 7.52(d, 2H),7-hydroxy-1H-benzoimidazole- phenyl]-2-dimethyl- 7.35˜7.25(m, 3H),6.77(d, 1H), 4.08(s, 2H), 4-carboxylic acid{2-[4-(2- amino-acetamide3.73(s, 2H), 2.97(m, 8H) dimethylamino-acetylamino)-phenyl]-ethyl}-amide 159 6 2-(2-chloro-4-fluoro-phenyl)-N-[4-(2-amino-ethyl)- 2 δ 7.94˜7.82(m, 2H), 7.60(d, 1H), 7.52(d, 2H),7-hydroxy-1H-benzoimidazole- phenyl]-2-diethylamino- 7.40(t, 1H),7.28(d, 2H), 6.89(d, 1H), 4.08(s, 4-carboxylic acid{2-[4-(2- acetamide2H), 3.68(t, 2H), 3.31(q, 4H), 2.94(t, 2H), diethylmaino-acetylamino)-1.34(t, 6H) phenyl]-ethyl}-amide 160 7 2-(3-chloro-4-fluoro-phenyl)-N-[4-(2-amino-ethyl)- 2 (1H, d), 7.90(1H, m), 7.72(1H, d), 7.47(2H, d),7-hydroxy-1H-benzoimidazole- phenyl]-p-toluene- 7.39(1H, m),7.13-7.06(4H, m), 6.95(2H, d), 4-carboxylic acid{2-[4- sulfonamide6.75(1H, d), 3.63(2H, t), 2.85(2H, t), 2.23(3H, s)(toluene-4-sulfonylamino)- phenyl]-ethyl}amide 161 72-(3-chloro-4-fluoro-phenyl)- N-[4-(2-amino-ethyl)- 2 δ 8.19(1H, d),7.95(1H, m), 7.74(1H, d), 7-hydroxy-1H-benzoimidazole- phenyl]-methane-7.42(1H, t), 7.24(2H, d), 7.13(2H, d), 6.75(1H, 4-carboxylic acid[2-(4-sulfonamide d), 3.68(2H, t), 2.91(2H, t), 2.81(3H, s)methanesulfonylamino-phenyl)- ethyl]-amide 162 17-hydroxy-2-phenyl-1H-benzo- n-butylamine 3 δ 7.95-7.70(2H, m), 7.69(1H,d), 7.60-7.42(1H, 309 imidazole-4-carboxylic acid m), 7.41-7.23(2H, m),3.42(2H, t), butylamide 1.78-1.56(2H, m), 1.55-1.34(2H, t), 0.97(3H, t)163 1 7-Hydroxy-2-phenyl-1H-benzo- 1,3-diaminopropane 3 δ 8.10(1H, d),7.90(1H, d), 7.68(1H, d), 310 imidazole-4-carboxylic acid 37.67-7.53(3H, m), 6.81(1H, d), 3.65(2H, t), (3-amino-propyl)-amide3.22-3.00(2H, t), 2.05(2H, t) 164 1 7-hydroxy-2-phenyl-1H-benzo-1-(3-aminopropyl)-2- 3 δ 8.04(1H, d), 7.81(1H, d), 7.75-7.66(3H, m), 378imidazole-4-carboxylic acid prolidinone 6.96(1H, d), 6.87(1H, d),3.53-3.41(6H, m), [3-(2-oxo-prolidine-1-yl)- 2.39(2H, t), 2.03(2H, t),1.90(2H, m) propyl]-amide 165 1 7-hydroxy-2-phenyl-1H-benzo-1-(3-aminopropyl)- 3 δ 9.05(1H, s), 8.17(2H, d), 7.84(1H, d), 7.75(1H,361 imidazole-4-carboxylic acid imidazole s), 7.72-7.62(3H, m), 7.55(1H,s), 6.88(1H, d), (3-imidazol-1-yl-propyl)- 4.40(2H, t), 3.57(2H, t),2.28(2H, m) amide 166 1 7-hydroxy-2-phenyl-1H-benzo- 4-(3-aminopropyl)-3 δ 8.10-8.11(2H, m), 7.86(2H, d), 380 imidazole-4-carboxylic acidmorpholine 7.84-7.69(1H, m), 7.63-7.59(2H, m), 4.10(2H,(3-morpholine-4-yl-propyl)- t), 4.06(2H, t), 3.80(2H, t), 3.65(2H, t),amide 3.54(2H, t), 3.15(2H, t), 2.14(2H, m) 167 17-hydroxy-2-phenyl-1H-benzo- 3-(2-methyl-imidazol-1-yl)- 3 δ8.18-8.11(2H, m), 7.84(1H, d), imidazole-4-carboxylic acid propylamine7.73-7.63(4H, m), 7.40(1H, d), 6.89(1H, d), [3-(2-methyl-imidazol-1-yl)-4.28(2H, t), 3.59(2H, t), 2.63(3H, s), 2.25(2H, m) propyl]-amide 168 22-(4-chloro-phenyl)-7-hydroxy- n-butylamine 3 δ 8.10(2H, d), 7.88(1H,d), 7.66(2H, d), 6.92(1H, 343 1H-benzoimidazole-4-carboxylic d),3.42(2H, t), 1.78-1.56(2H, m), acid butylamide 1.55-1.34(2H, t),0.97(3H, t) 169 2 2-(4-chloro-phenyl)-7-hydroxy- 1-(3-aminopropyl)-2- 3δ 8.21-8.11(2H, m), 7.82(1H, d), 7.63-7.53(2H, 4121H-benzoimidazole-4-carboxylic pyrrolidone m), 6.86(1H, m),3.60-3.38(6H, m), 2.38(2H, acid[3-(2-oxoprolidin-1-yl)- t), 2.03(2H, t),1.89(2H, m) propyl]-amide 170 2 2-(4-chloro-phenyl)-7-hydroxy-1-(3-aminopropyl)- 3 δ 9.03(1H, d), 8.18(2H, t), 7.81(1H, d), 7.74(1H,395 1H-benzoimidazole-4-carboxylic imidazole d), 7.64-7.53(3H, m),6.84(1H, d), 4.40(2H, t), acid(3-imidazole-1-yl-propyl)- 3.60(2H, t),2.29(2H, m) amide 171 2 2-(4-chloro-phenyl)-7-hydroxy-4-(3-aminopropyl)- 3 δ 8.21-8.10(2H, m), 7.85(1H, d), 4141H-benzoimidazole-4-carboxylic morphorine 7.61-7.54(2H, m), 6.80(1H, d),4.05(2H, t), acid(3-morphorine-4-yl-propyl)- 3.81(2H, t), 3.68-3.46(4H,m), 3.17(2H, t), amide 2.11(2H, m) 172 2 2-(4-chloro-phenyl)-7-hydroxy-3-(2-phenyl-imidazol-1-yl)- 3 δ 8.13(2H, d), 7.87(1H, d), 7.70(1H, d),473 1H-benzoimidazole-4-carboxylic propylamine 7.64-7.53(5H, m),7.47-7.25(3H, m), 6.80(1H, acid[3-(2-pentyl-imidazol-1- d), 4.41(2H, t),3.53(1H, t), 2.27(2H, m) yl)-propyl]-amide 173 22-(4-chloro-phenyl)-7-hydroxy- 3-(4-methyl-imidazole-1- 3 δ 8.85(1H, d),8.17(2H, t), 7.87(1H, m), 409 1H-benzoimidazole-4-carboxylicyl)-propylamine 7.68-7.57(2H, m), 7.40(1H, d), 6.89(1H, d),acid[3-(4-methyl-imidazol-1- 4.32(2H, t), 3.59(2H, m), 2.37-2.20(5H, m)yl)-propyl]-amide 174 2 2-(4-chloro-phenyl)-7-hydroxy-3-(4,5-dichloro-imidazole- 3 δ 8.13(2H, t), 7.85-7.78(2H, m),7.65-7.55(2H, 474 1H-benzoimidazole-4-carboxylic 1-yl)-propylamine m),6.87(1H, d), 4.18(2H, t), 3.54(2H, m), acid[3-(4,5-dichloro-imidazol-2.18(2H, m) 1-yl)-propyl]-amide 175 2 2-(4-chloro-phenyl)-7-hydroxy-3-(2-methyl-imidazole- 3 δ 8.21-8.09(3H, m), 7.68(1H, d), 4211H-benzoimidazole-4-carboxylic 1-yl)-propylamine 7.60-7.55(3H, m),7.36(1H, d), 4.28(2H, t), acid[3-(2-methyl-imidazol-1- 3.63(2H, m),2.60(3H, s), 2.28(2H, m) yl)-propyl]-amide 176 32-(2,4-dichloro-phenyl)-7- n-butylaine 3 δ 8.10(2H, d), 7.88(1H, d),7.66(2H, d), 377 hydroxy-1H-benzoimidazole-4- 7.37-7.23(4H, m), 6.92(1H,d), 3.42(2H, t), carboxylic acid butylamide 1.78-1.56(2H, m),1.55-1.34(2H, t), 0.97(3H, t) 177 3 2-(2,4-dichloro-phenyl)-7-1-(3-aminopropyl)-2- 3 δ 8.07-7.74(3H, m), 7.73-7.49(1H, m), 6.90(1H,446 hydroxy-1H-benzoimidazole-4- pyrolidione d), 3.60-3.38(6H, m),2.38(2H, t), 2.03(2H, t), carboxylic acid[3-(2-oxo- 1.89(2H, m)pyrolidin-1-yl)-propyl]-amide 178 3 2-(2,4-dichloro-phenyl)-7-1-(3-aminopropyl)- 3 δ 9.02(1H, s), 7.90-7.72(4H, m), 7.64-7.46(2H, 429hydroxy-1H-benzoimidazole-4- imidazole m), 6.88(1H, d), 4.37(2H, t),3.53(2H, t), carboxylic acid(3-imidazol-1- 2.26(2H, m) yl-propyl)-amide179 3 2-(2,4-dichloro-phenyl)-7- 4-(3-aminopropyl)- 3 δ 8.03-7.76(3H,m), 7.75-7.45(1H, m), 6.85(1H, 448 hydroxy-1H-benzoimidazole-4-morphorine d), 4.05(2H, t), 3.81(2H, t), 3.68-3.46(4H, m), carboxylicacid(3-morphorin- 3.17(2H, t), 2.11(2H, m) 4-yl-propyl)-amide 180 32-(2,4-dichloro-phenyl)-7- 3-(2-phenyl-imidazol-1- 3 δ 8.15(d, 2H),8.11(s, 1H), 7.86(s, 1H), hydroxy-1H-benzoimidazole-4- yl)-propylamine7.64˜7.29(m, 5H), 7.29˜7.25(m, 3H), 6.56(d, carboxylic acid[3-(2-phenyl-1H), 4.41(t, 2H), 3.53(t, 2H), 2.27(q, 3H) imidazol-1-yl)-propyl]-amide181 3 2-(2,4-dichloro-phenyl)-7- 3-(4-methyl-imidazol-1- 3 δ 8.84(s,1H), 7.91˜7.73(m, 3H), 7.58(m, 1H), hydroxy-1H-benzoimidazole-4-yl)-propylamine 7.38(s, 1H), 6.85(d, 1H), 4.29(t, 2H), 3.54(t, 2H),carboxylic acid[3-(4-methyl- 2.34˜2.25(m, 5H)imidazol-1-yl)-propyl]-amide 182 3 2-(2,4-dichloro-phenyl)-7-3-(4,5-dichloro-imidazol-1- 3 δ 7.91˜7.81(m, 4H), 7.52(s, 1H), 6.96(d,1H), hydroxy-1H-benzoimidazole-4- yl)-propylamine 4.15(t, 2H), 3.64(t,2H), 2.13(q, 2H) carboxylic acid[3-(4,5-dichloro-imidazol-1-yl)-propyl]-amide 183 3 2-(2,4-dichloro-phenyl)-7-3-(2-methyl-imidazol-1- 3 δ 8.11˜8.09(m, 3H), 7.61(m, 2H), 7.45(s, 1H),hydroxy-1H-benzoimidazole-4- yl)-propylamine 6.88(d, 1H), 4.31(t, 2H),3.46(t, 2H), 2.25(q, carboxylic acid[3-(2-methyl- 2H), 2.33(s, 3H)imidazol-1-yl)-propyl]-amide 184 3 2-(2,4-dichloro-phenyl)-7-3-(2-isopropyl-imidazol- 3 δ 8.10˜8.05(m, 3H), 7.58(m, 2H), 7.40(s, 1H),hydroxy-1H-benzoimidazole-4- 1-yl)-propylamine 6.88(d, 1H), 4.22(t, 2H),3.60(t, 2H), 3.02(m, carboxylic acid[3-(2- 1H), 1.3(s, 6H)isopropyl-imidazol-1-yl)- propyl]-amide 185 42-(4-fluoro-phenyl)-7-hydroxy- 1-(3-aminopropyl)- 3 δ 8.89(1H, s),8.21(2H, m), 7.83(1H, d), 1H-benzoimidazole-4-carboxylic imidazole7.49(1H, s), 7.38-7.24(3H, m), 6.90(1H, d),acid(3-imidazol-1-yl-propyl)- 4.31(2H, t), 3.56(2H, t), 2.38-2.33(2H, m)amide 186 4 2-(4-fluoro-phenyl)-7-hydroxy- 3-(2-isopropyl-imidazol- 3 δ8.26-8.21(2H, m), 7.84(1H, d), 7.65(1H, 1H-benzoimidazole-4-carboxylic1-yl)-propylamine s), 7.46-7.37(3H, m), 6.88(1H, d), 4.34(2H, t),acid[3-(2-isopropyl-imidazol- 3.62(2H, t), 3.52-3.43(1H, m), 2.27(2H,m), 1-yl)-propyl]-amide 1.36(6H, d) 187 4 2-(4-fluoro-phenyl)-7-hydroxy-3-(4-methyl-imidazole- 3 δ 8.89(1H, s), 8.21(2H, m), 7.83(1H, d),1H-benzoimidazole-4-carboxylic 1-yl)-propylamine 7.43(3H, m), 6.90(1H,d), 4.31(2H, t), 3.56(2H, acid[3-(4-methyl-imidazol-1- t), 2.38-2.27(5H,m) yl)-propyl]-amide 188 4 2-(4-fluoro-phenyl)-7-hydroxy-3-(2-methyl-imidazol- 3 δ 8.29(2H, m), 7.78(1H, d), 7.49(1H, s),1H-benzoimidazole-4-carboxylic 1-yl)-propylamine 7.35-7.24(3H, m),6.70(1H, d), 4.26(2H, t), acid[3-(2-methyl-imidazol-1- 3.64(2H, t),2.95(3H, s), 2.28(2H, m) yl)-propyl]-amide 189 42-(4-fluoro-phenyl)-7-hydroxy- 3-(2-ethyl-imidazol- 3 δ 8.27(2H, m),7.79(1H, d), 7.51(1H, s), 1H-benzoimidazole-4-carboxylic1-yl)-propylamine 7.33-7.25(3H, m), 6.72(1H, d), 4.27(2H, t),acid[3-(2-ethyl-imidazol-1- 3.65(2H, t), 2.90(2H, q), 2.28(2H, m),1.25(3H, t) yl)-propyl]-amide 190 4 2-(4-fluoro-phenyl)-7-hydroxy-3-(4,5-dichloro-imidazol-1- 3 δ 8.24-8.16(2H, m), 8.04(1H, d), 7.79(1H,d), 1H-benzoimidazole-4-carboxylic yl)-propylamine 7.45-7.33(2H, m),6.99-6.84(1H, m), 4.18(2H, acid[3-(4,5-dichloro-imidazol- t), 3.54(2H,t), 2.18(2H, m) 1-yl)-propyl]-amide 191 5 2-(2,4-difluoro-phenyl)-7-3-(2-isopropyl-imidazol- 3 δ 8.20(1H, q), 8.18-7.97(1H, m), 7.86(1H, d),hydroxy-1H-benzoimidazole-4- 1-yl)-propylamine 7.64(1H, s), 7.45(1H, s),7.39-7.24(1H, m), carboxylic acid[3-(2-isopropyl)- 6.86(1H, d), 4.33(2H,t), 3.60(2H, t), 3.49(1H, imidazol-1-yl)-propyl]-amide m), 2.26(2H, t),1.36(3H, s), 1.34(3H, s) 192 5 2-(2,4-difluoro-phenyl)-7-1-(3-aminopropyl)- 3 δ 8.23(1H, q), 7.13-7.97(1H, m), 7.84(1H, d),hydroxy-1H-benzoimidazole-4- imidazole 7.74(1H, s), 7.56(1H, s),7.31-7.24(2H, m), carboxylic acid(3-imidazol-1- 6.84(1H, d), 4.40(2H,t), 3.56(2H, t), 2.28(2H, t) yl-propyl)-amide 193 52-(2,4-difluoro-phenyl)-7- 3-(4-methyl-imidazol- 3 δ 8.22(1H, q),8.14-7.98(1H, m), 7.84(1H, d), hydroxy-1H-benzoimidazole-4-1-yl)-propylamine 7.40-7.27(3H, m), 6.85(1H, d), 4.30(2H, t), carboxylicacid[3-(4-methyl- 3.57(2H, t), 2.30(5H, m) imidazol-1-yl)-propyl]-amide194 5 2-(2,4-difluoro-phenyl)-7- 3-(4,5-dichloro-imidazol- 3 δ8.19-8.03(2H, m), 7.81(2H, m), hydroxy-1H-benzoimidazole-4-1-yl)propylamine 7.39-7.29(1H, m), 6.85(1H, d), 4.17(2H, t), carboxylicacid[3-(4,5-dichloro- 3.52(2H, t), 2.16(2H, t)imidazol-1-yl)-propyl]-amide 195 5 2-(2,4-difluoro-phenyl)-7-3-(2-methyl-imidazol- 3 δ 8.21(1H, q), 8.06(1H, m), 7.85(1H, d),hydroxy-1H-benzoimidazole-4- 1-yl)-propylamine 7.62(1H, s),7.39-7.27(2H, m), 6.87(1H, d), carboxylic acid[3-(2-methyl- 4.30(2H, t),3.58(2H, t), 2.63(3H, s), 2.25(2H, t) imidazol-1-yl)-propyl]-amide 196 52-(2,4-difluoro-phenyl)-7- 3-(2-ethyl-imidazol-1- 3 δ 8.29-8.05(2H, m),7.86(1H, d), 7.64(1H, s), hydroxy-1H-benzoimidazole-4- yl)-propylamine7.43(1H, s), 7.38-7.31(1H, m), 6.95(1H, d), carboxylic acid[3-(2-ethyl-4.29(2H, t), 3.57(2H, t), 3.03(2H, q), 2.25(2H, t),imidazol-1-yl)-propyl]-amide 1.34(3H, t) 197 52-(2,4-difluoro-phenyl)-7- 3-(4,5-dichloro-imidazol-1- 3 8.19-8.03(2H,m), 7.81(2H, m), hydroxy-1H-benzoimidazole-4- yl)-propylamine7.39-7.29(1H, m), 6.85(1H, d), 4.17(2H, t), carboxylicacid[3-(4,5-dichloro- 3.52(2H, t), 2.16(2H, t)imidazol-1-yl)-propyl]-amide 198 6 2-(2-chloro-4-fluoro-phenyl)-1-(3-aminopropyl)- 3 δ 9.05(1H, s), 8.00-7.88(2H, m), 7.74(1H, s),7-hydroxy-1H-benzoimidazol-4- imidazole 7.66-7.57(2H, m), 7.46-7.41(1H,m), 6.95(1H, carboxylic acid(3-imidazol-1- d), 4.38(2H, t), 3.52(2H, t),2.25(2H, t) yl-propyl)-amide 199 6 2-(2-chloro-4-fluoro-phenyl)-3-(4-methyl-imidazol-1- 3 δ 8.88(1H, s), 8.00-7.87(2H, m), 7.60(1H, m),7-hydroxy-1H-benzoimidazol-4- yl)-propylamine 7.41(2H, m), 6.94(1H, d),4.28(2H, t), 3.54(2H, carboxylic acid[3-(4-methyl- t), 2.29(3H, s),2.22(2H, t) imidazol-1-yl)-propyl]-amide 200 62-(2-chloro-4-fluoro-phenyl)- 3-(4,5-dichloro-imidazol- 3 δ 7.94(1H, m),7.85(1H, m), 7.76(1H, s), 7-hydroxy-1H-benzoimidazol-4-1-yl)-propylamine 7.48(1H, d), 7.30(1H, t), 6.76(1H, d), 4.17(2H, t),carboxylic acid[3-(4,5-dichloro- 3.56(2H, t), 2.16(2H, t) imidazol-1-yl)-propyl]-amide 201 6 2-(2-chloro-4-fluoro-phenyl)-3-(2-methyl-imidazol- 3 δ 7.83(1H, m), 7.50(1H, m), 7.39(1H, s),7-hydroxy-1H-benzoimidazol-4- 1-yl)-propylamine 7.23(2H, m), 7.13(1H,s), 6.76(1H, d), 4.20(2H, carboxylic acid[3-(2-methyl- t), 3.57(2H, t),2.47(3H, s), 2.03(2H, t) imidazol-1-yl)-propyl]-amide 202 72-(3-chloro-4-fluoro-phenyl)- 3-(4-methyl-imidazol-1- 3 δ 8.87(1H, s),8.37(1H, d), 8.17(1H, m), 7-hydroxy-1H-benzoimidazol-4- yl)-propylamine7.83(1H, d), 7.59(1H, t), 7.40(1H, s), 6.84(1H, carboxylicacid[3-(4-methyl- d), 4.33(2H, t), 3.60(2H, t), 2.25(5H, m)imidazol-1-yl)-propyl]-amide 203 7 2-(3-chloro-4-fluoro-phenyl)-1-(3-aminopropyl)- 3 δ 9.05(1H, s), 8.37(1H, d), 8.17(1H, m),7-hydroxy-1H-benzoimidazol-4- imidazol 7.83(1H, m), 7.75(1H, s),7.61-7.43(2H, m), carboxylic acid(3-imidazol-1- 6.82(1H, d), 4.41(2H,t), 3.60(2H, t), 2.30(2H, t) yl-propyl)-amide

EXAMPLE 204 Preparation of7-hydroxy-2-[4-(2-morpholin-4-yl-ethylamino)-phenyl]-1H-benzoimidazole-4-carboxylicacid [3-(4,5-dichloro-imidazol-1-yl)-propyl]-amide (1) Preparation of3-[(4-nitro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester

Anhydrous p-toluenesulfonic acid (6.30 g, 33.1 mmol) was added to 50 mlof benzene and the resulting mixture was refluxed while removing waterusing a dean-stock trap. Added thereto were 3-amino-4-methoxy benzoicacid methyl ester (3 g, 16.6 mmol) obtained in step 1 of PreparationExample 1 and 4-nitrobenzonitrile (2.94 g, 19.9 mol), followed bystirring at 160° C. for 8 hours. The resulting solution was cooled toroom temperature, the reaction was stopped by adding NaHCO₃ thereto,extracted with ethyl acetate, the extract was dried over MgSO₄ andconcentrated under a reduced pressure. The resulting residue waspurified by silica gel column chromatography to obtain the titlecompound (2.83 g, 8.59 mmol) in a yield of 52%.

¹H NMR (CDCl₃): δ 8.12-8.09 (m, 2H), 7.82 (d,1H), 7.70-7.69 (m, 1H),6.98 (d, 1H), 4.91 (bs, 2H), 3.89(s, 6H)

(2) Preparation of2-(4-nitro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methylester

3-[(4-nitro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester(1.63 g, 4.95 mmol) was dissolved in 50% methanol, and 5% NaOCl wasadded dropwise thereto at room temperature. After checking the reactionby TLC, Na₂CO₃ (1.05 g, 9.38 mmol) seas added dropwise thereto andrefluxed for 40 min. The resulting solution was cooled to roomtemperature, extracted with ethyl acetate and the extract wasconcentrated under a reduced pressure. The resulting residue waspurified by silica gel column chromatography to obtain the titlecompound (0.75 g, 2.28 mmol) in a yield of 46%.

¹H NMR (CDCl₃): δ 10.90 (bs, 1H), 8.36-8.31 (m, 4H), 7.95 (d, 1H), 6.78(d, 1H), 4.16 (s, 3H), 4.01 (s, 3H)

(3) Preparation of2-(4-amino-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid

2-(4-nitro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methylester (0.63 g, 1.92 mmol) obtained in step 2 was dissolved in 15 ml ofEtOH, 0.1 g of 10% Pd/C was added thereto and stirred for 24 hours whilehydrogen was supplied thereto from a balloon fulfilled with H₂ gas. Theresulting solution was filtered and dried to obtain the title compound(0.57 g, 1.92 mmol) in a yield of 100%.

¹H NMR (CH₃OH-d₄): δ 10.48 (bs, 1H), 7.93 (d, 2H), 7.82 (d, 1H), 6.77(d, 2H), 6.71 (d, 1H), 4.11 (s,3H), 3.98 (s, 3H)

(4) Preparation of2-[(2-morpholinoethyl)-4-amino-phenyl]-7-methoxy-1H-benzoimidazole-4-carboxylicacid methyl ester

2-(4-amino-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (160mg, 0.54 mmol) obtained in step 3 was dissolved in DMF, cesium carbonate(0.53 g, 1.61 mmol) was added thereto and stirred for 5 min. Addedthereto were 2-chloroethylmorpholine (0.12 g, 0.64 mmol) and potassiumiodide (0.18 g, 1.08 mmol), followed by stirring for 24 hours. Then, theresulting solution was extracted with ethyl acetate, the extract wasconcentrated under a reduced pressure, and the residue was purified bysilica gel chromatography to obtain the title compound (91 mg, 0.22mmol) in a yield of 41%.

¹H NMR (CH₃OH-d₄): δ 7.97 (d, 1H), 7.57 (d, 2H), 6.77-6.73 (m, 3H), 4.54(t, 2H), 4.11 (s, 3H), 3.99 (s, 3H), 3.57-3.55(m, 4H), 2.64 (t, 2H),2.31-2.28 (m, 4H)

(5) Preparation of2-[(2-morpholinoethyl)-4-amino-phenyl]-7-methoxy-1H-benzoimidazole-4-carboxylicacid-[3-(4,5-dichloro-imidazol-1-yl)-propyl]-amide

2-[(2-morpholinoethyl)-4-amino-phenyl]-7-methoxy-1H-benzoimidazole-4-carboxylicacid methyl ester (22 mg, 0.05 mmol) was dissolved in THF/H₂O, LiOHH₂O(6.7 mg, 0.16 mmol) was added thereto and stirred at room temperature.The resulting solution was filtered to remove residual LiOHH₂O, and thesolvent was removed. The residue was dried and dissolved in DMF. Addedthereto were 4,5-dichloro-1-(3-aminopropyl)imidazole (12.5 mg, 0.06mmol), EDCI (30.9 mg, 0.16 mmol), DMAP (65.6 mg, 0.54 mmol) and HOBt(21.8 mg, 0.16 mmol), followed by stirring at room temperature. Theresulting solution was extracted with ethyl acetate and concentratedunder a reduced pressure. The resulting residue was purified by silicagel chromatography to obtain the title compound (19 mg, 0.03 mmol) in ayield of 63%.

¹H NMR (CH₃OH-d₄): δ 7.93 (d, 1H), 7.77-7.75 (m, 3H), 7.52 (d, 2H), 6.92(d, 1H), 4.17 (t, 2H), 4.06-4.02 (m, 5H), 3.58-3.56 (m, 4H), 3.50 (t,2H), 2.66 (t, 2H), 2.31-2.29 (m, 4H), 2.16 (q, 2H)

(6) Preparation of2-[(2-morpholinoethyl)-4-amino-phenyl]-7-hydroxy-1H-benzoimidazole-4-carboxylicacid-[3-(4,5-dichloro-imidazol-1-yl)-propyl]-amide

2-[(2-morpholinoethyl)-4-amino-phenyl]-7-methoxy-1H-benzoimidazole-4-carboxylicacid-[3-(4,5-dichloro-imidazol-1-yl)-propyl]-amide (15 mg, 0.03 mmol)obtained in step 5 was dissolved in MC, BBr₃ (1.0M solution in MC, 0.3mL, 0.3 mmol) was added thereto and stirred at room temperature for 48hours. The reaction was stopped by adding water thereto and theresulting solution was extracted with MC/MeOH (7:1). The extract wasconcentrated under a reduced pressure and purified by silica gelchromatography to obtain the title compound (5.9 mg, 0.01 mmol) in ayield of 40%.

¹H NMR (CH₃OH-d₄): δ 7.95 (d, 1H), 7.81-7.79 (m, 4H), 7.55 (d, 1H), 6.94(d, 1H), 4.15 (t, 2H), 3.94 (t, 2H), 3.59 (t, 2H), 3.58-3.56 (m, 4H),2.64 (t, 2H), 2.32-2.30 (m, 4H), 2.18 (q, 2H)

TEST EXAMPLE 1 Assay for GSK-3β Inhibiting Activity

The GSK-3β inhibiting activity was determined in accordance with themethod of Shultz et al. described in U.S. Pat. No. 6,153,618, with minormodifications by using phospho-CREB peptide as a substrate.

First, PCR (polymerase chain reaction) was carried out using human DNAas a template as well as primers which were designed to correspond tothe 3′- and 5′ ends of the polynucleotide coding human GSK-3β gene(Genbank Accession No.: L33801). The BamH1/XhoI fragment of theamplified PCR product thus obtained was inserted into the pGex vectorbetween the BamH1 and XhoI sites, and the vector obtained wastransformed into E. coli BL21(DE3). The transformed cells thus obtainedwas incubated in LB agar plates (1% Bacto-trypton, 0.5% yeast extract,1% NaCl) containing ampicillin (100 μl/ml) until the optical density at600 nm reached about 0.5. The cultured mixture was cooled to 18° C. andisopropyl β-D-thiogalacto-pyranoside (IPTG) was added thereto to a finalconcentration of 0.5 mM. After 16 hours, the resultant was centrifugedat 10,000×g for 10 min, the collected cells were suspended in a buffersolution (30 mM Tris-HCl (pH 7.5), 100 mM NaCl, 5% glycerol, 2 mM DTT)and the cells were disrupted using Sonic Dismembrator (Fisher, U.S.A.)in a ice bath. The resulting solution was centrifuged at 16,000 rpm for30 minutes. The supernatant was connected to GST(Glutathione-S-transferase) column (Pharmacia Biotech, U.S.A.)equilibrated in the same buffer solution, purified by glutathioneaffinity chromatography (eluent: 5 mM glutathione), and then, digestedwith thrombin to cleave the connecting site between the GST moiety andGSK-3β protein. The purified GSK-3β protein was diluted in a buffersolution (20 mM HEPES (pH 7.5), 5% glycerol, 2 mM DTT) to a finalconcentration of 50 mM NaCl and the resulting solution was subjected tomono S column chromatography (eluent: linear gradient from 0M to 1M NaClbuffer) using mono S column (Pharmacia Biotech, U.S.A.) equilibrated inthe same buffer solution to obtain GSK-3β protein.

100 nM GSK-3β protein, 12.5 mM each of the compounds prepared inExamples 1 to 204 dissolved in DMSO, an assay buffer (50 mM Tris-HCl, pH7.5, 10 mM MgCl₂, 1 mM EGTA, 1 mM DTT), 100 μM phospho-CREB peptide(NEB, USA), 100 μM ATP, ³²P-ATP and 1 μCi were reacted at 30° C. for 1hour. The reaction was stopped by adding 5 μl of 5% phosphoric acid to25 μl of the resulting solution. The resulting mixture was centrifugedat 15,000 rpm for 10 min, 20 μl of the supernatant was added dropwise toWhatman p81 filter paper, and then, the resulting filter paper waswashed with 0.5% phosphate buffer for 10 min. The filter paper wasfurther washed 3 times and the enzymatic activity was determined byexamining the extent of phospho-CREB peptide phosphorylation which isrepresented by the unit of count per minute (CPM), measured with acounter (Packard, USA).

The GSK-3β inhibiting activity was then calculated in accordance withthe following equation:$\text{Degree~~of~~Inhibition(\%)} = {100 \times \left\lbrack {1 - \frac{\text{CPM(sample)} - \text{CPM(blank)}}{\text{CPM(control)} - \text{CPM(blank)}}} \right\rbrack}$wherein the blank represents a value obtained without the use of theenzyme and the compound of the present invention, and the control, inthe absence of the compound of the present invention.

The IC₅₀ value of the inventive compound was determined from the degreeof inhibition (%) and the result is shown in Table 3. TABLE 3 Ex- IC₅₀IC₅₀ IC₅₀ IC₅₀ am. (μM) Exam. (μM) Exam. (μM) Exam. (μM) 1 >1 52 >1103 >5 154 >1 2 >1 53 >1 104 >1 155 >1 3 >1 54 >1 105 0.05 156 0.28 4 >155 >1 106 0.015 157 0.49 5 0.3 56 0.7 107 0.05 158 0.23 6 >1 57 0.58108 >1 159 0.68 7 >1 58 0.67 109 0.03 160 >1 8 >1 59 0.16 110 0.28 1610.09 9 0.18 60 0.35 111 >1 162 0.24 10 0.04 61 >1 112 0.04 163 >1 11 >562 >1 113 0.19 164 0.84 12 0.2 63 0.45 114 0.001 165 0.08 13 0.36 640.03 115 0.026 166 >1 14 >1 65 0.06 116 0.003 167 0.1 15 0.11 66 >1 1170.03 168 >1 16 0.7 67 0.16 118 >5 169 >1 17 0.24 68 0.017 119 >5 1700.19 18 >1 69 >1 120 0.07 171 >1 19 >1 70 >1 121 0.03 172 0.8 20 4.171 >1 122 0.2 173 0.1 21 >5 72 0.12 123 0.05 174 0.04 22 >1 73 >1 1240.07 175 0.28 23 0.68 74 >1 125 >1 176 0.45 24 >5 75 0.009 126 >1 1770.2 25 >1 76 0.05 127 0.18 178 0.04 26 >1 77 0.033 128 0.15 179 >1 27 >178 >1 129 0.12 180 0.21 28 0.74 79 0.12 130 0.33 181 0.03 29 0.08 800.07 131 0.17 182 0.008 30 >1 81 >1 132 0.19 183 0.06 31 >1 82 >1 133 >1184 0.15 32 0.5 83 >1 134 0.04 185 >1 33 >1 84 >1 135 >1 186 0.05 34 >185 >5 136 0.24 187 0.01 35 0.007 86 0.25 137 0.005 188 0.002 36 >1 870.23 138 >1 189 >1 37 >1 88 0.22 139 0.12 190 0.006 38 >1 89 0.32 140 >1191 0.09 39 >1 90 0.13 141 0.043 192 0.008 40 >1 91 >1 142 0.001 1930.02 41 >1 92 0.08 143 0.002 194 0.004 42 >1 93 >1 144 0.006 195 0.0343 >1 94 >5 145 0.002 196 0.02 44 >1 95 >1 146 0.07 197 0.003 45 0.02 960.022 147 0.21 198 0.02 46 >5 97 0.17 148 >1 199 0.01 47 >5 98 >1 1490.14 200 0.002 48 >5 99 1 150 0.06 201 0.07 49 0.6 100 0.2 151 0.4 2020.009 50 0.6 101 >1 152 0.24 203 0.003 51 0.87 102 0.23 153 0.05 204 >5

While the invention has been described with respect to the abovespecific embodiments, it should be recognized that various modificationsand changes may be made to the invention by those skilled in the artwhich also fall within the scope of the invention as defined by theappended claims.

1. A compound of formula (I), and a pharmaceutically acceptable salt,hydrate, solvate or isomer thereof:

wherein: n is 0, 1, 2 or 3; R¹, R² and R³ are each independentlyhydrogen, hydroxy, halogen or morpholin-1-yl-ethylamino; R⁴ and R⁵ areeach independently hydrogen; linear or cyclic C₁-C₆ alkyl optionallyhaving one or more substituents, the carbon of the alkyl beingoptionally replaced with nitrogen, sulfur or oxygen, wherein thesubstituent is: hydroxy; halogen; allyloxy; alkyl; amino; alkylamino;carboxyl; nitro; sulfonylamido; alkanesulfonyl; amido; an aromatic groupoptionally having one or more substituents selected from the groupconsisting of hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino,carboxyl, nitro, amido, dioxoisoindole and sulfonylamino; an aromaticgroup having one or more substituents selected from the group consistingof hydroxy, halogen, alkyloxy, alkyl, amino, alkylamino, carboxyl, nitroand amido, the aromatic ring having nitrogen, sulfur or oxygen; orcyclic C₃-C₈ alkyl optionally having one or more substituents selectedfrom the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino,alkylamino, carboxyl, nitro and amido; an aromatic group optionallyhaving one or more substituents, the aromatic ring having optionalnitrogen, sulfur or oxygen, wherein the substituent is; hydroxy;halogen; alkyloxy; alkyl; amino; alkylamino; carboxyl; nitro;sulfonylamido, alkanesulfonyl; amido; or linear or cyclic C₁-C₆ alkyloptionally having one or more substituents, the alkyl having an optionalnitrogen, sulfur or oxygen linkage and the substiuent of the alkylbeing: hydroxy; halogen; alkyloxy; alkyl; amino; alkylamino; carboxyl;nitro; sulfonylamido, alkanesulfonyl; amido; an aromatic groupoptionally having one or more substituents selected from the groupconsisting of hydroxy; halogen; alkyloxy; alkyl; amino; alkylamino;carboxyl; nitro; amido; dioxoisoindole; and a sulfonylamino having anaromatic group substituted with hydroxy, halogen, alkyloxy, alkyl,amino, alkylamino, carboxyl, nitro, sulfonylamido, alkanesulfonyl oramido; an aromatic group optionally having one or more substituentsselected form the group consisting of hydroxy, halogen, alkyloxy, alkyl,amino, alkylamino, carboxyl, nitro, sulfonylamide, alkanesulfonyl andamido, the aromatic ring containing nitrogen, sulfur or oxygen; or acyclic C₃-C₈ alkyl optionally having one or more substituents selectedfrom the group consisting of hydroxy, halogen, alkyloxy, alkyl, amino,alkylamino, carboxyl, nitro and amido; or form, together with the—N-(CH₂)_(n)— moiety to which they are attached, a nitrogen heterocycleoptionally having one or more substituents selected from the groupconsisting of OH, NH₂, NO₂, the heterocycle containing optional nitrogenor oxygen.
 2. The compound of claim 1, wherein R⁴ and R⁵ are eachindependently hydrogen; C₁-C₄ alkyl optionally having one or moresubstituents selected from the group consisting of OH, NH₂, NO₂, and anaromatic group, the aromatic group optionally having one or moresubstituents selected from the group consisting of OH, C₁-C₄ alkyloxy,NH₂, NO₂, methanesulfonylamino, ethanesulfonylamino,tolunensulfonylamino and dioxoisoindole; cyclic C₃-C₈ alkyl optionallyhaving one or more substituents selected from the group consisting ofOH, NH₂ and NO₂; C₁-C₄ alkyl carrying a morpholine or oxopyrolidinegroup which is optionally substituted with OH, NH₂, NO₂ or —O—; C₁-C₄alkyl or C₁-C₄ aminoalkyl carrying a pyrrol, pyrazole, imidazole,1,2,3-triazole, 1,2,4-triazole, isoxazole, oxazole, isotiazole,tiazolidine, tiazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole,1,2,5-thiodiazole, 1,2,3-thiodiazole, 1,3,4-oxadiazole,1,3,4-thiodiazole, pyridine, pyrimidine or triazine group which isoptionally having one or more substituents selected from the groupconsisting of Cl, OH, NH₂, NO₂, C₁-C₄ and phenyl; cyclic C₃-C₈ alkyloptionally having one or more substituents selected from the groupconsisting of OH, NH₂ and NO₂; an aromatic group optionally having oneor more substituents selected from the group consisting of OH; NH₂;hydroxyalkyl; aminoalkyl; NO₂; and a C₁-C₄ alkyl group optionally havingone or more substituents selected from the group consisting of OH, NH₂,NO₂, methanesulfonylamino, ethanesulfonylamino, tolunensulfonylamino,dioxoisoindole and thiophensulfonylamino; or form, together with the—N—(CH₂)_(n)— moiety to which they are attached, a nitrogen heterocycleoptionally having one or more substituents selected from the groupconsisting of OH, NH₂ and NO₂, the heterocycle containing 1 to 3nitrogen, sulfur or oxygen atom.
 3. The compound of claim 1, wherein R⁴and R⁵ are each independently hydrogen; C₁-C₄ alkyl optionally havingone or more substituents selected from the group consisting of OH, NH₂,NO₂, morpholine, nitropyridineamino, pyridine, oxopyrolidin, imidazoleoptionally having a Cl, CH₃ or phenyl substituent; and phenyl optionallyhaving one or more substituents selected from the group consisting ofOH, NH₂, methoxy, NO₂, methanesulfonylamino, ethanesulfonylamino,tolunensulfonylamino and dioxoisoindole; cyclic C₃-C₈ alkyl optionallyhaving one or more substituents selected from the group consisting ofOH, NH₂ and NO₂; phenyl optionally having one or more substituentsselected from the group consisting of OH; NH₂; NO₂; and C₁-C₄ alkyloptionally having a OH, NH₂, NO₂, methanesulfonylamino,ethanesulfonylamino, tolunensulfonylamino, dioxoisoindole orthiophensulfonylamino substituent; or form, together with —N—(CH₂)_(n)—moiety to which they are attached, a piperidine ring optionally havingone or more substituents selected from the group consisting of OH, NH₂and NO₂.
 4. A process for preparing the compound of formula (IA) whichcomprises the steps of: reacting 3-amino-4-methoxy benzoic acid(compound II) and an alcohol to obtain compound (III); adding anhydrousp-toluenesulfonic acid and benzonitrile to the compound (III) thusobtained, refluxing the mixture at 80 to 200° C., adding NaOCl theretoat room temperature and purifying by silica gel column chromatography toobtain compound (IV); dissolving the compound (IV) thus obtained in analcohol, adding an aqueous alkali solution thereto and refluxing themixture to obtain compound (V); dissolving the compound (V) thusobtained in an organic solvent, adding a Lewis acid thereto andrefluxing the mixture to obtain compound (VI); dissolving the compound(V) thus obtained in alcohol, adding a strong acid thereto at roomtemperature and refluxing the mixture to obtain compound (VII);dissolving the compound (VII) thus obtained and(4-bromomethylphenoxy)-methyl polystyrene Wang resin in an organicsolvent, adding a base and KI thereto and stirring the mixture at 50 to60° C. for 1 to 24 hours to obtain compound (VIII); dissolving thecompound (VIII) thus obtained in an organic solvent, adding an alcoholsolution of an alkali hydroxide thereto and refluxing the mixture toobtain compound (IX); dissolving the compound (IX) thus obtained in anorganic solvent, adding R⁴N(CH₂)_(n)R⁵ and a coupling agent thereto andstirring the mixture at room temperature to obtain compound (X); anddissolving the compound (X) thus obtained in CH₂Cl₂, addingtrifluoroacetic acid thereto and stirring the mixture at roomtemperature to obtain compound (Ia).

wherein, n, R¹, R², R³, R⁴ and R⁵ have the same meaning as defined inclaim
 1. 5. A process for preparing the compound of formula (Ib) whichcomprises the steps of: reacting 3-amino-4-methoxy benzoic acid(compound II) and an alcohol to obtain compound (III); addingp-toluenesulfonic acid, benzene and 4-nitrobezonitrile thereto,refluxing the mixture at 80 to 200° C., adding NaOCl thereto at roomtemperature and purifying by silica gel column chromatography to obtaincompound (XI); dissolving the compound (XI) thus obtained in an organicsolvent, adding an aqueous alkali solution thereto, refluxing themixture and purifying by silica gel column chromatography to obtaincompound (XII); dissolving the compound (XII) thus obtained in analcohol, adding Pd/C thereto and refluxing the mixture to obtaincompound (XIII); dissolving the compound (XIII) thus obtained in anorganic solvent, adding a base, 2-chloroethylmorphine and potassiumiodide thereto and stirring the mixture at room temperature to obtaincompound (XIV); dissolving the compound (XIV) obtained thus in anorganic solvent, adding an alkali hydrate, stirring the mixture at roomtemperature to obtain compound (XV); dissolving the compound (XV) thusobtained in an organic solvent, adding4,5-dichloro-1-(3-aminoprophyl)imidazole and a coupling agent, stirringthe mixture at room temperature and purifying by silica gel columnchromatography to obtain compound (XVI); and dissolving the compound(XVI) thus obtained in MC, adding a Lewis acid thereto, stirring themixture, concentrating the resulting solution under a reduced pressureand purifying by silica gel column chromatography to obtain compound(Ib):

wherein, n, R¹, R², R³, R⁴ and R⁵ have the same meaning as defined inclaim
 1. 6. A pharmaceutical composition for inhibiting GSK-3βcomprising a therapeutically effective amount of the compound of claim 1and a pharmaceutically acceptable carrier.